CA2872260C - Heteroaryl-ketone fused azadecalin glucocorticoid receptor modulators - Google Patents

Abstract

The present invention provides heteroaryl ketone fused azadecalin compounds and methods of using the compounds as glucocorticoid receptor modulators.

Description

HETEROARYL-KETONE FUSED AZADECALIN GLUCOCORTICOID RECEPTOR
MODULATORS
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Application Nos.
61/781,269. filed March 14, 2013, 61/759,520, filed February 1, 2013, 61/715,907, filed October 19, 2012, 61/691,083, filed August 20, 2012, and 61/651,669, filed May 25, 2012.
BACKGROUND OF THE INVENTION
.. [0002] In most species, including man, the physiological glucocorticoid is cortiso]
(hydrocortisone). Glucocorticoids are secreted in response to ACTH
(corticotropin), which shows both circadian rhythm variation and elevations in response to stress and food. Cortisol levels are responsive within minutes to many physical and psychological stresses, including trauma, surgery, exercise, anxiety and depression. Cortisol is a steroid and acts by binding to .. an intracellular, glucocorticoid receptor (GR). In man, glucocorticoid receptors are present in two forms: a ligand-binding GR-alpha of 777 amino acids; and, a GR-beta isoform which lacks the 50 carboxy terminal residues. Since these include the ligand binding domain, GR-beta is unable to bind ligand, is constitutively localized in the nucleus, and is transcriptionally inactive.
The GR is also known as the GR-II receptor.
[0003] The biologic effects of cortisol, including those caused by hypercortisolemia, can be modulated at the GR level using receptor modulators, such as agonists, partial agonists and antagonists. Several different classes of agents are able to block the physiologic effects of GR-agonist binding. These antagonists include compositions which, by binding to GR, block the ability of an agonist to effectively bind to and/or activate the GR. One such known GR
antagonist, mifepri stone, has been found to be an effective anti-glucocorticoid agent in humans (Bertagna (1984) 1 Clin. Endocrinol. Metab. 59:25). Mifepristone binds to the GR with high affinity, with a dissociation constant (Kd) of 10-9 M (Cadepond (1997)Annu.
Rev. Med.
48:129).

What is needed in the art are new compositions and methods for modulating GR
receptors.
Surprisingly, the present invention meets these and other needs.
BRIEF SUMMARY OF THE INVENTION
[00041 The present invention provides many fused azadecalin compounds. In some embodiments, the present invention provides compounds having the structure of formula I:

N N(CH2), =
(R2)1-4 I
R3 (.1) wherein RI of formula I is a heteroaryl ring having from 5 to 6 ring members and from 1 to 4 heteroatoms which can each independently be N, 0 or S, optionally substituted with 1-4 groups which can each independently be R. Each RI' of formula I can independently be hydrogen, C1_6 alkyl, halogen, Cj_6 haloalkyl, Ci.6 alkoxy, CI-6 haloalkoxy, -CN, N-oxide, C3-8 cycloalkyl, or C3_8 heterocycloalkyl. Ring J of formula I can be a cycloallcyl ring, a heterocycloalkyl ring, an aryl ring or a heteroaryl ring, wherein the heterocycloalkyl and heteroaryl rings have from 5 to 6 ring members and from 1 to 4 heteroatoms which can each independently be N, 0 or S.
Each R2 of formula I can independently be hydrogen, C1_6 alkyl, halogen, C1.6 haloalkyl, C1_6 alkoxy, C1.6 haloallwxy, C1.6 alkyl-C1.6 alkoxy, -CN, -OH, -NR 2aR2h, -C(0)R28, -C(0)0R28 , _c(0)NR21R2b, K S(0)R2a, -S(0)2R2, C2-8 cyeloalkyl, and C3-8 heterocycloalkyl, wherein the heterocycloalkyl groups are optionally substituted with 1-4 R2' groups.
Alternatively, two R2 groups linked to the same carbon can be combined to form an oxo group (=0).
Alternatively, two R2 groups can be combined to form a heterocycloalkyl ring having from 5 to 6 ring members and from 1 to 3 heteroatoms wherein each can independently be N, 0 or S.
wherein the heterocycloalkyl ring is optionally substituted with from 1 to 3 R2"

groups. R2a and R2b of formula I can each independently be hydrogen or Ci..6 alkyl. Each R2 can independently be hydrogen, halogen, hydroxy, C1.6 alkoxy, C1.6 haloalkoxy, -CN, or -NR2b. Each R2d can independently be hydrogen or Ci_6 alkyl, or two R2d groups attached to the same ring atom can be combined to form (...0). R3 of formula I can be phenyl or pyridyl, each optionally substituted with 1-4 R3fi groups. Each R38 of formula I can independently be hydrogen, halogen, or

2 C1_6 haloalkyl. Subscript n of formula I can be an integer from 0 to 3. The compounds of formula I can also be the salts and isomers thereof.
[00051 In some embodiments, the present invention provides a pharmaceutical composition including a pharmaceutically acceptable excipient and the compound of formula I.
[00061 In some embodiments, the present invention provides a method of modulating a glucocorticoid receptor, the method including contacting a glucocorticoid receptor with a compound of formula I, thereby modulating the glucocorticoid receptor.
100071 In some embodiments, the present invention provides a method of treating a disorder through modulating a glucocorticoid receptor, the method including administering to a subject in need of such treatment, a therapeutically effective amount of a compound of formula I, thereby treating the disorder.
[00081 In some embodiments, the present invention provides a method of treating a disorder through antagonizing a glucocorticoid receptor, the method including administering to a subject in need of such treatment, an effective amount of the compound of formula I, thereby treating the .. disorder.
BRIEF* DESCRIPTION OF THE DRAWINGS
100091 Figures 1 and 2 show various synthetic schemes for making the compounds of the present invention.

DETAILED DESCRIPTION OF THE INVENTION
I. General [00101 The present invention provides compounds capable of modulating a glucocorticoid receptor (OR) and thereby providing beneficial therapeutic effects. The compounds include heteroaryl ketone fused azadecalins. The present invention also provides methods of treating diseases and disorders by modulating a GR receptor with the compounds of the present invention.

3 IL Definitions [00111 The abbreviations used herein have their conventional meaning within the chemical and biological arts.
100121 Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left. e.g., -CH20- is equivalent to -OCH2-.
100131 "Alkyl" refers to a straight or branched, saturated, aliphatic radical having the number of carbon atoms indicated. Alkyl can include any number of carbons, such as C.
C1-3, C14, C1-5, C1-6, C1-7, C1-8, C1-9, C1-10, C2-3, C2-4, C2-5, C2-6, C34, C3-5, C3-6, C4-5, C. and C5-6. For example, Cl_o alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec_butyl, teitbutyl, pentyl, isopentyl, hexyl, etc. Alkyl can also refer to alkyl groups having up to 20 carbons atoms, such as, but not limited to heptyl, octyl, nonyl, decyl, etc.
00141 "Alkylene" refers to a straight or branched, saturated, aliphatic radical having the number of carbon atoms indicated, and linking at least two other groups, i.e., a divalent hydrocarbon radical. The two moieties linked to the alkylene can be linked to the same atom or different atoms of the alkylene group. For instance, a straight chain alkylene can be the bivalent radical of -(CH2),-, where n is 1, 2, 3, 4, 5 or 6. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene and hexykne.
100151 "Alkoxy" refers to an alkyl group having an oxygen atom that connects the alkyl group to the point of attachment: alkyl-O-. As for the alkyl group, alkoxy groups can have any suitable number of carbon atoms, such as C1_6. Alkoxy groups include, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, etc.
[00161 "Alkyl-Alkoxy" refers to a radical having an alkyl. component and an alkoxy component, where the alkyl component links the alkoxy component to the point of attachment.
The alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to link to the alkoxy component and to the point of attachment. The alkyl component can include any number of carbons, such as C0-6, C1.2, C1-3, C1-4, C1-5, C1-6, C2-3, C2-4, C2-5, C2-6,

4 C3-4, C3-5, C3-6, C4-5, C4-6 and C. In some instances, the alkyl component can be absent. The alkoxy component is as defined above.
100171 "Halogen" refers to fluorine, chlorine, bromine and iodine.
[00181 "Haloaflcyl" refers to alkyl, as defined above, where some or all of the hydrogen atoms .. are replaced with halogen atoms. As for the alkyl group, haloallcyl groups can have any suitable number of carbon atoms, such as C1_6. For example, haloallcyl includes trifluoromethyl, fluoromethyl, etc. In some instances, the term "perfluoro" can be used to define a compound or radical where all the hydrogens are replaced with fluorine. For example, perfluoromethane includes 1,1,1-trifluoromethyl.
100191 "Haloalkoxy" refers to an alkoxy group where some or all of the hydrogen atoms are substituted with halogen atoms. As for the alkyl group, haloalkoxy groups can have any suitable number of carbon atoms, such as C1-6. The alkoxy groups can be substituted with 1,2, 3, or more halogens. When all the hydrogens are replaced with a halogen, for example by fluorine, the compounds are per-substituted, for example, perfluorinated. Haloalkoxy includes, but is not limited to, trifluoromethoxy, 2,2,2,-trifluoroethoxy, perfluoroethoxy, etc.
[0020] "Cycloalkyl" refers to a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly containing from 3 to 12 ring atoms, or the number of atoms indicated. Cycloalkyl can include any number of carbons, such as C3-6, C4-6, C5-6, C3-8, C4-8, C.
C6-8, C3-9, C3-10, C3-11, and C3-12. Saturated monocyclic cycloallcyl rings include, for example, .. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbomane, [2.2.2]
bicyclooctane, decahydronaphthalene and adamantane. Cycloalkyl groups can also be partially unsaturated, having one or more double or triple bonds in the ring. Representative cycloalkyl groups that are partially unsaturated include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4- and 1,5-isomers), norbomene, and norbomadiene. When cycloalkyl is a saturated monocyclic C3.8 cycloalkyl, exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
When cycloalkyl is a saturated monocyclic C36 cycloalkyl, exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

5 [00211 "Alkyl-cycloalkyl" refers to a radical having an alkyl component and a cycloalkyl component, where the alkyl component links the cycloalkyl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to link to the cycloalkyl component and to the point of attachment. In some instances, the alkyl component can be absent. The alkyl component can include any number of carbons, such as Cc, C1-2, C1-3, C1-4, C1-5, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4.6 and C54. The cycloalkyl component is as defined within. Exemplary alkyl-cycloalkyl groups include, but are not limited to, methyl-cyclopropyl, methyl-cyclobutyl, methyl-cyclopentyl and methyl-cyclohexyl.
100221 "Heterocycloalkyl" refers to a saturated ring system having from 3 to 12 ring members and from 1 to 4 heteroatoms of N, 0 and S. Additional heteroatoms can also be useful, including, but not limited to, B, Al, Si and P. The heteroatoms can also be oxidized, such as, but not limited to, -S(0)- and -S(0)2-. Heterocycloalkyl groups can include any number of ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heterocycloalkyl groups, such aS 1, 2, 3, or 4, or 1 to 2, I to 3, I to 4, 2 to 3, 2 to 4, or 3 to 4. The heterocycloalkyl group can include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazol.idine, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxalidine, thiazolidine, isothiazol.idine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. The heterocycloalkyl groups can also be fused to aromatic or non-aromatic ring systems to form members including, but not limited to, indoline.
[00231 When heterocycloalkyl includes 3 to 8 ring members and I to 3 heteroatoms, representative members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, oxane, tetrahydrothiophene, thiane, pyrazolidine, imidazolidine, piperazine, oxazol.idine, isoxazolidine, thiazolidine, isothiazolidine, morpholine, thiomorpholine, dioxane and dithiane.
Heterocycloalkyl can also form a ring having 5 to 6 ring members and 1 to 2 heteroatoms, with representative members including, but not limited to, pyrrolidine, piperidine, tetrahydrofuran,

6 tetrahydrothiophene, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, and morpholine.
[00241 "Aryl" refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings. Aryl groups can include any suitable number of ring atoms, such as, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, as well as from 6 to 10, 6 to 12, or 6 to 14 ring members. Aryl groups can be monocyclic, fused to form bicyclic or tricyclic groups, or Linked by a bond to form a biaryl group. Representative aryl groups include phenyl, naphthyl and biphenyl. Other aryl groups include benzyl, having a methylene linking group.
Some aryl groups have from 6 to 12 ring members, such as phenyl, naphthyl or biphenyl.
Other aryl groups have from 6 to 10 ring members, such as phenyl or naphthyl. Some other aryl groups have 6 ring members, such as phenyl. Aryl groups can be substituted or unsubstituted.
100251 "Arylene" refers to an aryl group, as defined above, linking at least two other groups.
The two moieties linked to the aryl are linked to different atoms of the aryl.
Arylene groups can be substituted or unsubstituted.
[00261 "Heteroaryl" refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, where from 1 to 5 of the ring atoms are a heteroatom such as N, or S. Additional heteroatorns can also be useful, including, but not limited to, B, Al, Si and P.
The heteroatoms can also be oxidized, such as, but not limited to, -S(0)- and -S(0)2-. Heteroaryl groups can include any number of ring atoms, such as, 3 to 6,4 to 6, 5 to 6, 3 to 8,4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heteroaryl groups, such as 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5. Heteroaryl groups can have from 5 to 8 ring members and from 1 to 4 heteroatoms, or from 5 to 8 ring members and from 1 to 3 heteroatoms, or from 5 to 6 ring members and from 1 to 4 heteroatoms, or from 5 to 6 ring members and from 1 to 3 heteroatoms.
The heteroaryl group can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. The heteroaryl groups can also be fused to aromatic ring systems, such as a phenyl ring, to form members including, but not limited to, benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinawline), benzopyridazines such as

7 phthalazine and cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include heteroaryl rings linked by a bond, such as bipyridine. Heteroaryl groups can be substituted or unsubstituted.
[00271 The heteroaryl groups can be linked via any position on the ring. For example, pyrrole includes 1-, 2-and 3-pyrrole, pyridine includes 2-, 3- and 4-pyridine, imidazole includes 1-, 2-, 4- and 5-imidazole, pyrazole includes 1-, 3-, 4- and 5-pyrazole, triazole includes 1-, 4- and 5-triazole, tetrazole includes 1- and 5-tetrazole, pyrimidine includes 2-, 4-, 5-and 6- pyrimidine, pyridazine includes 3- and 4-pyridazine, 1,2,3-triazine includes 4- and 5-triazine, 1,2,4-triazine includes 3-, 5-and 6-triazine, 1,3,5-triazine includes 2-triazine, thiophene includes 2- and 3-thiophene, furan includes 2-and 3-furan, thiazole includes 2-, 4- and 5-thiazole, isothiazole includes 3-, 4- and 5-isothiazole, oxazole includes 2-, 4- and 5-oxazole, isoxazole includes 3-, 4-and 5-isoxazole, indole includes 1-, 2- and 3-indole, isoindole includes 1-and 2-isoindole, quinoline includes 2-, 3- and 4-quinoline, isoquinoline includes 1-, 3- and 4-isoquinoline, quinazoline includes 2- and 4-quinoazoline, cinnoline includes 3- and 4-cinnoline, benzothiophene includes 2- and 3-benzothiophene, and benzofuran includes 2-and 3-benzofuran.
[00281 Some heteroaryl groups include those having from 5 to 10 ring members and from Ito 3 ring atoms including N, 0 or S. such as pyrrole, pyridine, imidazole, pyrazole, tris7ole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include those having from 5 to 8 ring members and from 1 to 3 heteroatoms, such as pyrrol.e, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1.,2,3-, 1,2,4-and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Some other heteroaryl groups include those having from 9 to 12 ring members and from 1 to 3 heteroatoms, such as indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, benzofuran and bipyridine. Still other heteroaryl groups include those having from. 5 to 6 ring members and from. I to 2 ring heteroatoms including N, 0 or S.
such as pyrrole, pyridine, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, thiazole, isothiazole, oxazole, and isoxazole.

8

9 PCT/US2013/042732 [00291 Some heteroaryl groups include from 5 to 10 ring members and only nitrogen heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyrida7ine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, and cinnoline. Other heteroaryl groups include from 5 to

10 ring members and only oxygen heteroatoms, such as furan and benzofuran.
Some other heteroaryl groups include from 5 to 10 ring members and only sulfur heteroatoms, such as thiophene and benzothiophene. Still other heteroaryl groups include from 5 to 10 ring members and at least two heteroatoms, such as imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiazole, isothiazole, oxazole, isoxazole, quinoxaline, quinazoline, phthalazine, and cinnoline.
[00301 "Heteroarylene" refers to a heteroaryl group, as defined above, linking at least two other groups. The two moieties linked to the heteroaryl are linked to different atoms of the heteroaryl.
Heteroarylene groups can be substituted or unsubstituted.
[00311 "Salt" refers to acid or base salts of the compounds used in the methods of the present invention. Illustrative examples of pharmaceutically acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic propionic acid, glummic acid,, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in R.emington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.
[00321 "Hydrate" refers to a compound that is complexed to at least one water molecule. The compounds of the present invention can be complexed with from 1 to 10 water molecules.
[00331 "Isomers" refers to compounds with the same chemical formula but which are structurally distinguishable.
[00341 "Tautomer" refers to one of two or more structural isomers which exist in equilibrium.
and which are readily converted from. one form to another.
[00351 "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier"
refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, Naa., normal saline solutions, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors and colors, and the like. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present invention.
[00361 "Modulating a glucocorticoid receptor" refers to methods for adjusting the response of a glucocorticoid receptor towards glucocorticoids, glucocorticoid antagonists, agonists, and partial agonists. The methods include contacting a glucocorticoid receptor with an effective amount of either an antagonist, an agonist, or a partial agonist and detecting a change in OR
activity.
100371 "Glucocorticoid receptor" ("OR") refers to a family of intracellular receptors which specifically bind to cortisol and/or cortisol analogs (e.g. dexamethasone).
The glucocorticoid receptor is also referred TO as the cortisol receptor. The term includes isoforms of OR, recombinant OR and mutated OR.
100381 "Glucocorticoid receptor antagonist" refers to any composition or compound which partially or completely inhibits (antagonizes) the binding of a glucocorticoid receptor (OR) agonist, such as cortisol, or cortisol analogs, synthetic or natural, to a GR.
A. "specific glucocorticoid receptor antagonist" refers to any composition or compound which inhibits any biological response associated with the binding of a OR to an agonist. By "specific," we intend the drug to preferentially bind to the OR rather than other nuclear receptors, such as mineralocorticoid receptor (MR) or progesterone receptor (PR).
[00391 "OR modulator" refers to compounds that agonize and/or antagonize the glucocorticoid receptor and are defined as compounds of Formula I below.
[00401 "Anti-inflammatory glucocorticosteroid" refers to a class of steroid hormones that bind to the gl.ucocorticoid receptor and reduce inflammation. Examples of anti-inflammatory glucocorticosteroids include, but are not limited to, cortisol (the physiological glucocorticoid) as well as alclometasone, betamethasone, budesonide, ciclesonide, clobetasol, clocortolone, deprodone, desonide, dexatnethasone, difluprednate, flunisolide, fluocinolone, fluticasone, halcinonide, halometasone, halopredone, hydrocortisone, loteprednol, methylprednisolone, mometasone, naflocort, oxazacort, paramethasone, prednicarbate, prednisolone, prednisone, triamcinolone, trimexolone, and ulobetasol. Glucocorticosteroids are part of a class of compounds called corticosteroids that also includes mineralocorticosteroids.
The anti-inflammatory gluc,ocortic,osteroids of the present invention bind to glucocorticoid receptor and not to the mineralocorticoid receptor, also known as the glucocorticoid receptor 1 (GRI).
[00411 "GR induced transactivation" refers to gene expression induced by binding of a GR
agonist to a glucocorticoid receptor. For example, OR induced transactivation can occur when an anti-inflammatory glucocorticosteroid, such as dexamethasone, binds to a glucocorticoid receptor. In the present invention, inhibition of OR induced transactivation occurs with at least 25% inhibition of the OR induced transactivation activity.
100421 "GR induced transrepression" refers to inhibition of gene expression induced by binding of a GR agonist to a glucocorticoid receptor. The OR modulators of the present invention can have minimal effect on OR induced transrepression. In the present invention, substantially not inhibiting OR-induced transrepression is when OR-induced transrepression activity in the presence of the OR modulator is at least 50% of the activity observed in the absence of the OR modulator.
[00431 "Contacting" refers to the process of bringing into contact at least two distinct species such that they can react with one another or interact such that one has an effect on the other.
100441 "Treat", "treating" and "treatment" refer to any indicia of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient's physical or mental. well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation.
[00451 "Patient" or "subject in need thereof" refers to a living organism suffering from or prone to a condition that can be treated by administration of a pharmaceutical composition as Ii provided herein. Non-limiting examples include humans, other mammals and other non-mammalian animals.
[00461 "Disorder" or "condition" refer to a state of being or health status of a patient or subject capable of being treated with the glucocorticoid receptor modulators of the present invention.
Examples of disorders or conditions include, but are not limited to, obesity, hypertension, depression, anxiety, and Cushing's Syndrome.
100471 "Antagonizing" refers to blocking the binding of an agonist at a receptor molecule or to inhibiting the signal produced by a receptor-agonist. A receptor antagonist blocks or dampens agonist-mediated responses.
100481 "Therapeutically effective amount" refers to an amount of a conjugated functional agent or of a pharmaceutical composition useful for treating or ameliorating an identified disease or condition, or for exhibiting a detectable therapeutic or inhibitory effect.
The effect can be detected by any assay method known in the art.
100491 Description of compounds of the present invention are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and/or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, or physiological conditions.
111. Compounds [00501 The present invention provides many fused azadecalin compounds. In some embodiments, the present invention provides compounds having the structure of formula 1:
Ri 000 N/ N ,R2,1.4 wherein R1 of formula I is a heteroaryl ring having from 5 to 6 ring members and from 1 to 4 heteroatoms which can each independently be N, 0 or S, optionally substituted with 1-4 groups which can each independently be R1a. Each R18 of formula I can independently be hydrogen, C1,6 alkyl, halogen, C1.6 haloalkyl, C alkoxy, C1-6 haloalkoxy, -CN, N-oxide, C3-8 cycloalkyl, or C3_8 heterocycloalkyl. Ring J of formula I can be a cycloalkyl ring, a heterocycloalkyl ring, an aryl ring or a heteroaryl ring, wherein the heterocycloalkyl and heteroaryl rings have from 5 to 6 ring members and from 1 to 4 heteroatoms which can each independently be N, 0 or S.
Each R.2 of formula I can independently be hydrogen, C1.6 alkyl, halogen.
C1..6 haloalkyl, C1..6 allc.oxy, C1.6 haloalkoxy, C1.6 alkyl-Ci.6 alkoxy, -CN, -NR28R20, -C(0)R28, -C(0)0R2a, -C(0)NR2aR2b, SR20,-S(0)R28, -S(0)2.R2. C3..8 cycloalkyl, and C3.8 heterocycloalkyl, wherein the heterocycloalkyl groups are optionally substituted with 1-4 R2c groups.
Alternatively, two R.2 groups linked to the same carbon can be combined to form. an oxo group (=0).
Alternatively, two R2 groups can be combined to form a heterocycloalkyl ring having from 5 to 6 ring members and from I to 3 heteroatoms wherein each can independently be N, 0 or S, wherein the heterocycloalkyl ring is optionally substituted with from 1 to 3 R2a groups.
I(/' and le of formula I can each independently be hydrogen or C1.6 alkyl. Each R2c can independently be hydrogen, halogen, hydroxy, C1.6 alkoxy, C1_6 haloalkoxy, -CN, or -NR28R2b.
Each R26 can independently be hydrogen or C1.6 alkyl, or two R2d groups attaulted to the saute ring atoin um be combined to form (=0). R3 of formula! can be phenyl or pyridyl, each optionally substituted with 1-4 R38 groups. Each R38 of formula I can independently be hydrogen, halogen, or haloalkyl. Subscript n of formula! can be an integer from 0 to 3. The compounds of formula I can also be the salts and isomers thereof.
100511 In some embodiments, wherein R1 of formula 1 can be a heteroaryl ring having from 5 to 6 ring members and from 1 to 4 heteroatoms which can each independently be N, 0 or S, optionally substituted with 1-4 groups which can each independently be RIO.
Each Ria of formula I can independently be hydrogen, Ci_6 alkyl, halogen, C1.6 haloalkyl, Ci..6 alkoxy, C1.6 haloalkoxy, -CN, C3.,8 cycloalkyl., or C3.8 heterocycloalk.yl. RingJ of formula lean be a cycloalkyl ring, a heterocycloalkyl ring, an aryl ring or a heteroaryl ring, wherein the heterocycloalkyl and heteroaryl rings have from 5 to 6 ring members and from 1 to 3 heteroatoms which can each independently be N, 0 or S. Each R2 of formula I
can independently be hydrogen, C1.6 alkyl, halogen, C1..6 haloalkyl, C1.6 alkoxy, C1..6 haloalkoxy, -CN, .N.R2aR2b, cycloalkyl, or C3_8 heterocycloalkyl, wherein the heterocycloalkyl groups are optionally substituted with 1-4 R2c groups. R28 and R2b of formula 1 can each independently be hydrogen or C1.6 alkyl. Each R20 can independently be hydrogen, halogen, hydroxy, Cj_6 alkoxy, C1_6 haloalkoxy, -CN, or -NR2arsK2h.
R3 of formula I can be phenyl or pyridyl, each optionally substituted with 1-4 RR groups. Each R38 of formula I can independently be hydrogen, halogen, or C1..6 haloalkyl. Subscript n of formula I can be an integer from 0 to 3.
The compounds of formula I can also be the salts and isomers thereof.
100521 In some embodiments. R1 can be a heteroaryl ring having from 5 to 6 ring members and from 1 to 3 heteroatoms which each can independently be N, 0 or S. optionally substituted with 1-4 groups which can each independently be Rla. Each RIO can independently be hydrogen or Co alkyl. Ring J can be tetrahydrofitran, phenyl or pyridyl. Each R2 can independently be hydrogen, C1_6 alkyl, halogen, C1.6 haloalkyl, C1.6 alkoxy, Ci_6 haloalkoxy, _EN, _NR28R2b, C3-8 cycloalkyl., or C3.5 heterocycloalkyl. R28 and R2b can each independently be hydrogen or C1.6 alkyl. R.3 can be phenyl or pyridyl. R30 can be F. Subscript n can be 0 or 1. In some embodiments, each Rla can independently be hydrogen, C1-6 alkyl, C1.6 haloalkyl, or C1..6 alkoxy.
[00531 In some embodiments, RI can be a heteroaryl ring having from 5 to 6 ring members and from I to 3 heteroatoms which can each independently be N. 0 or S. optionally substituted with 1-4 groups which can each independently be RIO. Each RIO can independently be hydrogen or C1.6 alkyl. Ring J can be phenyl or pyridyl. Each R2 can independently be hydrogen, halogen, C1.6 haloalkyl, -CN or C5.6 heterocycloalkyl. R3 can be phenyl or pyridyl.
R.38 can be F. In some embodiments, each RIO can independently be hydrogen, C1-6 alkyl, C1.6 haloalkyl, or C1..6 alkoxy.
[00541 The compounds of the present invention include at least one stereogenic center at the bridgehead carbon. Accordingly, the compounds can include a mixture of isomers, including enantiomers in a racemic mixture, or in enantiomerically pure mixtures that are substantially the R- or S-isomer. In some embodiments, the compounds of formula 1 can have the following structure:

N'c,, = (R2)14 N I
:

[00551 Any suitable heteroaryl can be used for le in the compounds of the present invention, as defined in the definitions above. In some embodiments, the heteroaryl of le can have from 5 to 6 ring members and from I to 4 heteroatoms which can each independently be N, 0 or S, optionally substituted with 1-4 groups which can each independently be Ria. In some embodiments, the heteroaryl of R' can be pyrrole, pyrazole, imidazole, triazole, tetrazole, furan, oxazole, isoxazole, oxadiazole, thiophene, thiazole, isothiazole, thiadiazole, pyridine, pyrazine, pyrimidine, or pyridazine. In some embodiments, the heteroaryl of Rican be 2-pyrrole, 3-pyrrole, 1-pyrazole, 3-pyrazole, 4-pyrazole, 5-pyrazole, 2-imidazole, 4-imidazole, 5-imidazole, 1,2,3-triazol-4-yl, 1,2,3,-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,3,4-tetrazol-1-yl, 1,2,3,4,tetrazol-5-yl, 2-furan, 3-fiwan, 2-oxazole, 4-oxazole, 5-oxazole, 3-isoxazole, 4-isooxazole. 5-isooxazole, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, 2-thiophene, 3-thiophene, 2-thiazole, 4-thiazole, 5-thiazole. 3-isothiazole, 4-isothiazole, 5-isothiazole, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1,3,4-thiadiazol-2-yl, 2-pyridine, 3-pyridine, 4-pyridine, pyrazine, 2-pyrimidine, 4-pyrimidine, 5-pyrimidine, 6-pyrimidine, 3-pyridazine, 4-pyridazine, 5-pyridazine, or 6-pyridazine. In some embodiments, the heteroaryl of R' can be pyrazole, imidazole, triazole, furan, oxazole, oxadiazole, thiophene, thiazole, pyridine, pyrazine or pyrimidine. In some embodiments, the heteroaryl of RI can be imidazole, furan, oxazole, oxadiazole, thiophene, thiazole, or pyridine. In some embodiments, the heteroaryl of R1 can be 1-pyrazole, 3-pyrazole, 4-pyrazole, 5-pyrazole, 2-imidazole, 4-imidazole, 5-imidazole, 1,2,3-triazol-4-yl, 1,2,3,-triazol-5-yl, 1,2õ4-triazol-3-yl, 1,2,4-triazol-5-yl, 2-fiiran, 3-fiiran, 2-oxazole, 4-oxazole, 5-oxazole, 1õ2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, 2-thiophene, 3-thiophene, 2-thiazolc, 4-thiazole, 5-thiazolc, 2-pyridine, 3-pyridine, 4-pyridine, pyrazinc, 2-pyrimidine, 4-pyrimidine, 5-pyrimidine, or 6-pyrimidine. In some embodiments, the heteroaryl of Ie can be 3-pyrazole, 4-pyrazole, 2-imidazole, 1,2,4-triazol-5-yl, 2-furan, 2-oxazole, 4-oxazole, 1,3,4-oxadiazol-2-yl, 2-thiophene, 2-thiazole, 4-thiazole, 5-thiazole, 2-pyridine, 3-pyridine, 4-pyridine, pyrazine, or 2-pyrimidine. In some embodiments, the heteroaryl of R' can be 2-imidazole, 4-imidazole, 5-imidazole, 2-fiiran, 3-furan, 2-oxazole, 4-oxazole, 5-oxazole, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, 2-thiophene, 3-thiophene, 2-thiazole, 4-thiazole, 5-thiazole, 2-pyridine, 3-pyridine, or 4-pyridine.

[00561 in some embodiments, the heteroaryl of R1 can be optionally substituted with 1-4 groups which can each independently be R. In some embodiments, each R" can independently be hydrogen, C1_6 alkyl, halogen, C1_6 haloalkyl, C1-6 alkoxy, C1_6 haloalkoxy, -CN, N-oxide, C3-8 cycloalkyl, or C3-8 heterocycloalkyl. In some embodiments, each Rla can independently be hydrogen, C1.4 alkyl, Ci_6 haloalkyl, Ci_6 alkoxy or C3..8 heterocycloalkyl.
In some embodiments, each Rla can independently be hydrogen, C1-6 alkyl, C1.6 haloalkyl, or C1_6 alkoxy.
In some embodiments, each Rla can independently be hydrogen, C1.6 alkyl, or C1.6 haloalkyl. In some embodiments, each Rla can independently be hydrogen or C1.6 alkyl. The alkyl of Ria can be any suitable alkyl group, such as methyl, ethyl, propyl, butyl, pentyl, and hexyl, among others. In some embodiments, each RIO can independently be hydrogen, methyl, ethyl, trifluoromethyl, methoxy, or pyrrolidinyl. In som.e embodiments, each RIO can independently be hydrogen, methyl, ethyl, trifluoromethyl, or methoxy. In some embodiments, each RI' can.
independently be hydrogen or methyl.
[00571 Ring J of formula I can be any suitable ring. In som.e embodiments, ring J of formula I
can be a cycloalkyl ring, a heterocycloalkyl ring, an aryl ring or a heteroaryl ring, wherein the heterocycloalkyl and heteroaryl rings can have from 5 to 6 ring members and from 1 to 4 heteroatoms which can each independently be N, 0 or S. In some embodiments, ring J can be heterocycloallc.yl, aryl or heteroaryl. Suitable heterocycloalkyl groups include those defined in the definitions above. In some embodiments, the heterocycloalkyl can tetrahydrofuran. Suitable aryl groups for ring J include those defined in the definitions above.
Representative aryl groups include phenyl and naphthyl. In some embodiments, the aryl group of ring J can be phenyl..
Suitable heteroaryl groups for ring J include those defined in the definitions above.
Representative heteroaryl groups include pyrrole, pyridine, imidazol.e, pyrazole, triazole, tetrazolc, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thia.zole, isothiazole, oxazole, and isoxazole. In some embodiments, the heteroaryl can be pyridyl or thiophene. In some embodiments, ring .1 can be aryl or heteroaryl.
In some embodiments, ring j can be phenyl, pyridine, imidazole, pyrazole, triazole, tetrazole, thiadiazole, isothiazole, isoxazole, cyclohexyl, tetrahydrofiiran and tetrahydro-2H-pyran.
In some embodiments, ring j can be phenyl, pyridine, or pyrazole. In some embodiments, ring j can be tetrahydrofuran, phenyl, pyridyl or thiophene. In some embodiments, ring j can be phenyl. in some embodiments, ring J can be pyridyl. In some embodiments, ring .11 can be pyrazole.

[00581 in some embodiments, the heteroaryl of R1 can be 3-pyrazole, 4-pyrazole, 2-imidazole, 1,2,4-triazol-5-yl, 2-furan, 2-oxazole, 4-oxazole, 1,3,4-oxadiazol-2-yl, 2-thiophene, 2-thiazole, 4-thiazole, 5-thiazok, 2-pyridine, 3-pyridine, 4-pyridine, pyrazine, or 2-pyrimidine, and Ring J
can be 2-pyridine, 3-pyridine, 4-pyridine, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, 1,2,3-triazol-4-yl, isoxazol-4-yl, cyclohexyl, tetrahydroftiran or tetrahydro-2H-pyran.
[00591 Ring J of formula I can be substituted with any suitable number of R2 groups. Each R2 of formula I can independently be hydrogen, C1_6 alkyl, halogen. Ci_6 haloalkyl, C1_6 alkoxy, haloalkoxy, Ci..6 alkyl-C14 alkoxy, -CN, -OH, -NR22R2b, _go).-µ28,C(0)0R2a, -C(0)NR2aR2b, -SR28, -S(0)R28, -S(0)2R2a. C3..8 cycloalkyl, or C3-8 heterocycloalkyl, wherein the heterocycloalkyl groups are optionally substituted with 1-4 R2c groups. In some embodiments, each R.2 of formula I can independently be hydrogen, C1.6 alkyl, halogen, C
haloalkyl, C1..6 alkoxy, C1.6 haloalkoxy, CI .6 alkyl-C1.6 alkoxy, -CN, -NR.2aR2b, _C(0)OR 2a, -S(0)2R2a, C3.8 cycloalkyl, or C3.8 heterocycloalkyl, wherein the heterocycloalkyl group has 5-6 ring members and I to 2 heteroatoms. In some embodiments, each R2 of formula I can independently be hydrogen, C1.6 alkyl, halogen, C1..6 haloalkyl, C1.6 alkoxy, C1..6 haloalkoxy, C1..6 alkyl-Ci..6 alkoxy, -CN, -NR28R2b,S(O.)2R2a,C3.8 cycloalkyl, or C3_8 heterocycloalkyl, wherein the heterocycloalic.y1 group has 5-6 ring members and 1 to 2 heteroatoms. Each R2 of formula I can independently be hydrogen, C1.6 alkyl, halogen, C1.6 haloalkyl, C1..6 alkoxy, C1.6 haloalkoxy, -CN, -NR212.2b, C3.8 cycloalkyl, or C3_8 heterocycloalkyl, wherein the heterocycloalkyl groups are optionally substituted with 1-4 R2' groups. In some embodiments, each R2 can independently be hydrogen, halogen, C1.6 haloalkyl., -CN, or heterocycloalkyl having 5-6 ring members and 1 to 2 heteroatoms wherein at least one heteroatom is N. Heterocycloalkyl groups haying 5-6 ring members and 1 to 2 heteroatoms with at least one nitrogen include, but arc not limited to, pyrrolidine, piperidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3-and 1,4-isomers), oxazolidine, isoxalidine, thiazolidine, isothiazolidine, morpholine, or thiomorpholine. In some embodiments, each R2 can independently be hydrogen, methyl, ethyl, propyl, isopropyl, F, Cl, -CF3, CH20Me, OMe, OCHF2, -CN, -NMe2, -C(0)0H, -C(0)NMe2, -S(0)2Me, pyrrolidine, piperidine or morpholine. in some embodiments, each R2 can independently be hydrogen, methyl, ethyl, F, Cl, -CF3, OMe, OCHF2, -CN, -NMe2, -S(0)2Me, pyrrolidine, piperidine or morpholine. In some embodiments, each R2 can independently be hydrogen, F, -CF3, -CN, pyrrolidine, piperidine or morpholine. In some embodiments, R2 can be ¨CF3.
Ring J can be substituted with 1, 2, 3 or 4 R2 groups. In some embodiments, ring J is substituted with 1 R2 group.
[00601 Several R2 groups can be further substituted with one or more of R28, R2b and R2c. R28 and R21) can each independently be hydrogen or C14 alkyl. Each R2c can independently be hydrogen, halogen, hydroxy, C1.6 alkoxy, Ci_6 haloalkoxy, -CN, or -NR28R2b.
100611 R3 of formula 1 can be phenyl or pyridyl, each optionally substituted with 1-4 R30 groups. In some embodiments, R3 can be substituted with 1 R3a group. Each R3' group can independently be hydrogen, halogen, or Ci4 haloalkyl. In some embodiments, each R30 group can independently be H, F, Cl, Br, or ¨CF3. In some embodiments, each R3a group can independently be F or ¨CF3. In some embodiments, R3' can be F. The R3 group can be present at any position on the phenyl or pyridyl ring to form a 2-, 3- or 4-substituted ring. In some embodiments, the phenyl or pyridyl ring is substituted at the 4-position. In some embodiments, R.1 can be 4-F-phenyl.
.. [00621 When R3 of formula I is 4-F-phenyl, the compounds of the present invention can have the following structure:
RI 0 0, 0 R1 ,0 0 0 .R N" (CH2)r, N NICHA-40 2) N I (.. ,;-4 (R2)14N I
N
or F
Alternatively, the compounds of the present invention can have the following structure:
R1 0 0 0 R 1y0 p N:kfi eS
N I N (R2)1.4 'NC9¨(R2)14 or i 8 [00631 Subscript n of formula I can be an integer from 0 to 3. In some embodiments, subscript n can be 0, 1, 2, or 3. In some embodiments, subscript n can be 0 or 1. In some embodiments, subscript n can be 0. In some embodiments, subscript n can be 1.
[00641 In some embodiments, the compound of formula I can be:
Intermediate 13. (R)-(6-((6-chloropyridin-3-Asulfony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-g] isoquinolin-4a-y1)(pyridin-2-ypmethanone, Intermediate 14. (R)-(6-((6-chloropyridin-3-yOsulfony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(thiazol-2-yOmethanone, Example 1. (R)-(1-(4-fluoropheny1)-644-(trifluoromethypphenyl)sulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g] isoquinolin-4a-y1)(pyridin-2-ypmethanone, Example 1A. (R)-(1-(4-fluoropheny1)-644-(trifluoromethyl)phenyl)sulfony1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-g] isoquinolin-4a-y1)(1-methy1-1H-imidazol-2-yl)methanone, Example 1B. (R)-(144-fluoropheny1)-6-((4-(trilluoromethypphenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-cta-y1)(pridin-3-yOmethanone, Example IC. (R)-(144-fluoropheny1)-6-((4-(trilluoromethypphenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-IH-pyrazolop,4-disoquinolin-4a-y1)(thiazol-2-yOmethanone, Fx a mple. 1 D (R )-( 1 -(4-fliloropheny1)-64(4-(tri romethyl)ph enyl)sullony1)-4,4a ,5,6,7,R-hexahydro-11-1-pyrazolo[3,4-g] isoquinolin-4a-y1)(5-methyl-1,3,4-oxadiazol-2-yl)methanone, Example 1E. (12)-(1-(4-fluoropheny1)-64(44trifluoromethypphenypsulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo [3,4-g] i soqui nolin-4a-y1)(oxazol -4-yl)methan one, Example 1F. (R)-(1 -(4-fluoropheny1)-64(4-(trifluoromethyl)phenyl)sulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo [3,4-g] isoquinolin-4a-y1)(oxazol-2-Amethanone, Example 10. (R)-(1-(4-fluoropheny1)-6-04-(trifluoromethyl)phenypsulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo [3,4-g] isoqui nolin-4a-y1)(furan -2-yl)methanone, Example 1H. (R)-(1-(4-fluoropheny1)-6-04-(trifluoromethyl)phenypsulfony1)-4,4a,5,6,7,8-hexahydro- 1 H-pyrazolo[3,4-g] isoquinolin-4a-y1)(thiophen-2-Amethanone, Example 11. (R)-(1-(4-fluoropheny1)-6-(m-tolylsulfony1)-4,4a,5,6,7,8-hexahydro-pyrazolo[3,4-disoquinolin-4a-y1)(oxazol-2-yl)methanone, Example ii. (R)-( 1 -(4-fluoropheny1)-6-(m-tolylsulfony1)-4,4a,5,6,7,8-hexahydro- 1H-pyrazolo [3,4-g]isoquinolin-4a-yI)(pyrimidin-2-yl)methanone, Example 1K. (R)-(6((3,5-difluorophenyl)sulfony1)- 1 -(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-g]isoquinolin-4a-y1)(4-methoxypyridin-2-yOmethanone, Example IL. (R)-(4-ethylpyridin-2-y1)(1-(4-fluorophenyl)-6-03,4,5-trifluorophenyl)s ulfonyD-4,4a,5,6,7,8-hexahydro- 1 H-pyrazolo[3,4-g] isoquinolin-4a-yl)methanone, Example 1M. (R)-(1 -(4- fluoropheny1)-6-((3,4,5-tri fluorophenypsul fony1)-4,4a,5,6,7,8-hexahydro- 1 H-pyrazolo [3,4-g] isoqu inolin-4a-y1)(4-methoxypyridin-2-yl)methanone, Example 2. (R)-(I -(4-fluoropheny1)-64(4-fluorophenypsulfony1)4,41a,5,6,7,8-hexahydro- 1 H-pyrazolo [3,4-g] soquino lin-4a-y1)(pyridi n-2-yl)methanone, Example 2A. (R)-(6((3-fluorobenzyl)sulforiy1)-1 -(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro- 1 H-pyrazolo [3,4-g] soquinoli n-4a-y1)(thiazol -2-yl)methanone, Example 2B. ((ziaR)-1-(4-fluoropheny1)-64((R/S)-tetrahydrofttran-2-yl)methyl)sulfony1)-4,4a,5,6,7,8-hexahydro- 1 H-pyrazolo [3,4-di soquin ol in-4a-y1)(thiawl-2-yl)methanone, Example 2C. (R)-(1 -(4-fluoropheriy1)-6-(o-to1y1sulfony1)-4,4a,5,6,7,8-hexahydro- 1 H-pyrazolo [3,4-g] soquinoli n-4a-y1)(pyridi n-2-yl)methanorte, Example 2D. (R)-(6((4-ethylphenyl)sulfony1)- 1-(4-fluoropheny1)-4,40 ,6õ7,8-hexahydro- 1 H-pyrahulo[3,4-g]isoquinolio-4a-y1)(pyridin-2-y1)ifiethamoe, Example 2E. (R)-(1 -(4-fluoropheny1)-6-(m-tolyisulfony1)-4,4a,5,6,7,8-hexahydro- 1H-pyrazolo [3,4-g] soquino n-4a-yI)(pyridi n-2-yOmethanone, Example 2F. (R)-(6((3-chlorophenyl)sulfony1)- 1 -(4-fluompheny1)-4,4a,5,6,7,8-hex ahydro- 1 14-pyrazolo [3,4-g] isoquinolin-4a-y1)(pyridin-2-yOmethanone, Example 2G. (R)-( 1 -(4-flu oropheny1)-6-((3-methoxyphenypsulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g] isoquinolin-4a-y1)(pyridin-2-yl)methanone, Example 2H. (R)-(644-chloro-3-fluoropheny1)sulfony1)- 1-(4-fluoropheny1)-4,4a,5,6,7,8-hex ahydro- 1 H-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-Amethanone, Example 21. (R)-( 1 -(4-fluoropheny1)-644-methoxyphenyl)sulfony1)-4,4a,5,6,7,8-hexahydro- 1 H-pyrazolo [3,4-g] isoquiriolin-4a-y1)(pyridin-2-yl)methanone, Example 2J. (R)-(643-fluoro-4-meth.ylphertypsulfony1)-1 -(4-fluoropheny1)-44a,5,6,7,8-hexahydro- 1 H-pyrazolo[3,4-disoquino1in-4a-y1)(pyridin-2-y1)methanone, Example 2K. (R)-(1-(4-fluoropheny1)-6-(phenylsulfony1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-g]isoquinolin-4a-y1)(pyridin-2-y1)methanone, Example 2L. (R)-(1-(4-fluoropheny1)-64(2-fluorophertyl)sulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo [3,4-g] isoquinolin-4a-yI)(pyridin-2-yl)methanone, Example 2M. (R)-(1-(4-fluoropheny1)-64(1-methyl-1H-pyrazol-4-yl)su1fony1)-4,40,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-yl)methanone, Example 2N. (R)-(1-(4- fluoropheny1)-6-06-(tri fluoromethyl)pyridin-3-ypsul fon y1)-4,4a,5,6,7,8-hexah ydro-1H-pyrazol o[3,4-g] isoqu inolin-4a-y1)(ppidin-2-yl)methanone, Example 20. (R)-( I -(4-fluoropheny1)-6-tosyl-4,4a,5,6,7,8-hexahydro-1 H-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-Amethanone, Example 2P. (R)-(6-04-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-yl)methanone, Example 2Q. (R)-4-(0 -(4-fluoropheny1)-4a-picolinoy1-4a,5,7,8-tetrahydro-111-pyrazolo [3,4-disoquinoli n-6(4H)-y11sulfonyl )benzonitrile, Example 2R. (R)-(1-(4-fluoropheny1)-64(6-methoxypyridin-3-yl)sulfony1)-4,4a,5,6,7,8-hexahydro-IH-pyrazoloP,4-disoquinolin-4a-y1)(pyridin-2-yl)methanone, Example 2S. (R)-(1-(4-fluoropheny1)-6-((tetrahydro-2H-pyran-4-yl)sulfony1)-4,4a,5,6,7,8-hexahydi 0-1 EI-pyrdzolo[3,4-g]isoquilluliii-4a-y1)(pyridiu-2-yOmethaulum, Example 2T. (R)-(6-(cyclohexylsulfony1)-1-(4-fluoropheny1)-4,43,5,6,7,8-hexahyd ro-1H-pyrazolo [3,4-g] soquino n-4a-yI)(pyridi n-2-yOmethanone, Example 2U. (R )46-((1-ethyl - I H-pyrazol-5-yl)sul fony1)- 1-(4-fluoroph eny I)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo [3,4-g] isoquino lin-4a-y1)(4-(trifluoromethyppyridin-2-yl)methanone, Example 2V. (R)-(643,5-dimethy1-1H-pyrazol-4-y1)sulfony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo [3,4-g] isoquinolin-4a-yI)(4-(trifluoromethyl)pyridin-2-yl)meth anone, Example 2W. (R)-(6-((1H-imidazol-4-yl)sul fony1)-1-(4-fl uorophenyI)-4,4a,5,6,7,8-hexahydro-I H-pyrazolo[3,4-disoquinol in-4a-y1)(4-(trifluoromethyl)pyridin-2-yl)methanone, Example 3. (R)-(1-(4-fluoropheny1)-6-((6-morpholinopyridin-3-yDsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-yl)methanone, Example 4. (R)- ( I -(4-fluoropheny1)-64(6-(pyrrolidin - 1 -yl)pyridin-3-yOsulfony1)-4,4a,5,6,7,8-hexahydro- 1 H-pyrazolo [3,4-g] isoqui nolin-4a-y1)(thiazol-2-yptnethanone, Example 5. (R)-( I -(4-fluoropheny1)-6-((4-fluorophenyl)sulfony1)-4,4a,5,6,7,8-hexahydro- 1 H-pyrazolo [3,4-g] isoquinolin-4a-y1)(thiazol-2-yl)methanone, Example 5A. (R)-( 1 -(4-fluoropheny1)-6-((3-fluorophenyl)sulfony1)-4,4a,5,6,7,8-hexahydro- 1 H.
pyrazolo [3,4-g] isoquinolin-4a-y1)(thiazol-2-yOmethanone, Example 58. (R)-4-((( 1 -(4-fluorophen yI)-4a-(thi e-2-carbonyl )-4a.5,7,8-tetrahydro- 1 H-pyrazolo [3,4-g] isoquinol in-6(48)-yl)sulfonypmethyl)benzonitrile.
Example SC. (R)-( 1 4441 uoropheny1)-64(3-(trifl uorom ethyl)phenyl)sulfony1)-4,4a,5,6,7,8-1 0 hexahydro- 1 H-pyrazolo [3,4-g] isoquino lin-4a-yI)(pyridi n-2-yl)methanone, Example SD. (R)-( I -(4-fluoropheny1)-6-(4-(trifluoromethyl)phenyl)sulfony1)-4,4a,5,6,7,8-hexahydro- 1 H-pyrazol o[3,4-g] isoquinolin-4a-y1)( 1 -methyl- 1 H-1,2,4-triazol-5-yl)methanone, Example 5E. (R)-( 1 -(4-fluoropheny1)-6-44-(trifluoromethyl)phenyOsul fonyI)-4,4a,5,6,7,8-I 5 hex ahydro- 1 H-pyrazolo[3,4-disoquinolin-4a-y1)(pyrazin-2-yl)methanone, Example 5F. (R)-( 1 -(4-fluorophenyI)-6-((5-fluoropyridi n-3-yl)sul fonyl)-4,4a,5,6,7,8-hexahydro-I H-pyrazolo[3,4-g] isoquinolin-4a-y1)(pyridin-2-yl)methanone, Exam* 50. (R)-( 1 -(4-11uuruplicily1)-6-((3- fluotophenyl)sulfuny 1)-4,41,5,6,7,8-11exithy diu- 1 H-pyrazolo [3,4-g] isoquinoli n-4a-y I)(pyridi n-2-yl)methanone, 20 Example 58. (R)-( 1 -(4-fluoropheny1)-6-04-(trifluoromethyl)phenypsulfony1)-4,4a,5,6,7,8-hex ahydro- I H-pyrazolo[3,4-disoquinolin-4a-y1)(5-methoxymridin-2-yOmethanone, Example 51. (R)-( 1 -(4-fluoropheny1)-6-((4-(trifluoromethyl)phenypsulfonyl)-4,4a,5,6,7,8-hexahydro- 1 H-pyrazolo [3,4-g] isoquino lin-4a-y1)(thiazol-5-yl)methanone, Example 5.1. (R)-( 1 -(4-fluoropheny1)-645-fluoropyridin-3-yl)sulfony1)-4,4a,5,6,7,8-hexahydro-25 1H-pyrazolo[3,4-disoquinolin-4a-y1)(thiazol-2-yl)methanone, Example 6. (R)-(I -(4-fluoropheny1)-6-((4-(pyrrol idin- 1-yl)phenyl)sulfony1)-4,4a,5,6,7,8-hexahydro- 1 H-pyrazolo [3,4-g] isoquinolin-4a-y1)(thiazol-2-yptnethanone, Example 6A. (R)-( I -(4-fluoropheny1)-6-03-(pyrrolidin- I -yl)phenyl)su1fony1)-4,4a,5,6,7,8-hexahydro- 1 H-pyrazolo [3,4-g] isoquinolin-4 a-y1)(thi azol-2-y1)Inethanone, 30 Example 7. (R)-( 1 -(4-fluoropheny1)-6-05-(piperi din- 1 -yl)pyridin-3-yl)sul fonyI)-4,4a,5,6,7,8-hexah ydro-1 11-pyrazolo [3,4-g] isoque nolin-4a-y1)(thiazol -2-yl)methanone, Example 7A. (R)-(1-(4-fluorophenyI)- 6-05-(pyrrolidin-l-yl)pyridin-3-yl)sulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo [3,4-g] isoqui nolin-4a-y1)(thiazol-2-yOmethanone, Example 8. (R)-(1-(4-fluoropheny1)-6-06-(pyrrolidin-l-yppyridin-3-y1)sulfony1)-4,4a.5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-yOmethanone, Example 9. ((R)-1-(4-fluoropheny1)-6-06-((R)-3-fluoropyrrolidin- 1 -Apyridin-3-yl)sulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-d isoquinolin-4a-yD(thiazo 1-2-yl)methanone, Example 10. (R)-(1-(4-fluoropheny1)-6-04-(pyrroli di n- I -yl)phenypsulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(pridin-2-yl)methanone, Example 10A. (R)-(1-(4-fluoropheny1)-64(5-(piperidin- 1 -yl)pyrid in-3-yl)s ulfony1)-4,4 a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-yl)methanone, Example 10B, (R)-(1-0-fluoropheny1)-6-45-(pyrrolidin-1-yppyridin-3-y1)sulfonyl)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-y1)methanone, Example 11. 00-(1-0-fl uoropheny1)-6-((4 -(trifluorom ethy Ophenyl)sul fony1)-4,4a,5,6,7,8-hexah ydro-1H-pyrazolo [3,4-0 isoquinolin-4a-y1)(thiazol-4-yOmethanone, Example 11A. (R)-(6((4-chlorophenypsul fony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-bexahydro-lH-pyrazolo [3,4-g] soquinoli n-4a-y1)(pyridi n-2-yl)methanone, Example 11B. (R)-(1-(4-fluoropheny1)-6-((4-methoxy-3-methylphenyl)sulfony1)-4,4a,5,6,7,8-lamallytho-1H-pylazolu[3,4-g]isoquilluliii-4a-y1)(pyt idiu-2-yOmethaulum, Example 11C. (R)-(6-((3-chloro-4-methoxyphenyl)su Ifony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-1H-pyrazo I o [3,4-g] soqui noli n-4a-y1)(pyri di n-2-y pmeth anone, Example 11 D. (R)-(6-03-fluoro-4-methoxyphenybsulfony1)-1-(4-fluoropheny1)-4,4a,5,6.7,8-hexahydro-1H-pyrazolo [3,4-g] isoquino lin-4a-y1)(pyridin-2-yl)methanone, Example 11E. (R)-(642-fluoro-4-methylphenypsulfony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo [3,4-g] isoquino lin-4a-y1)(pyridin-2-yOmethanone, Example 11F. (R)-(1-(4-fluoropheny1)-6-(m-tolyisulfony1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo [3,4-g] isoquin oli n-4a-y1)(thiazol-4-yl)methanone, Example 11G. (R)-3-((1-(4-fl uoropheny1)-4a-picolinoyl -4a,5,7,8-tetrahydro-1H-pyrazolo [3,4-gi isoqui nolin-6(4H)-yl)sulfonyl)benzonitrile, Example 11H. (R)-(6-04-(difluoromethoxy)phenyl)sulfony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo [3,4-g] soqui nol in-4a-y I)(pyridin-2-yl)methanone, Example 111. (R)-(1 -(4-fluoropheny1)-6-03-(trifluoromethoxy)phenyl)sulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo [3,4-g] isoqui nolin-4a-y I)( pyridin-2-yl)methanone, Example 11J. (R)-(6-((3,5-difluorophenyl)sulfony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-yl)methanone, Example 11K. (R)-(1-(4-fluoropheny1)-6-tosyl-44a,5,6,7,8-hexahydro- 1H-pyrazolo[3,4-disoquinolin-4a-y1)(thiazol-4-yl)methanone, Example I IL. (R)-(6-03-(difluoromethoxy)phenyl)sulfony1)-1 -(4- fluoropheny1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g] isoqu inolin-4a-y1)(pridi n-2-yl)meth arione, Example I 1M. (R)-(6-((3,4-dimeth.ylphertypsulfony1)-1-(4-fittoropheny1)-4,4a,5,6,7,8-liexahydro-IH-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-y1)methanone, Example 1 IN. (R)-(6-((3,5-dimethylphenypsulfony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-yl)methanone, Example 110. (R)-(1-(4-fluoropheny1)-646-methylpyridin-2-ypsulfony1)-4,4a,5,6,7,8-hexAydro-IH-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-yOmethanone, Example 11P. (R)-(64(3,4-difluoropheny1)sulfony1)-144-fluoropheny1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-yl)methanone, Example 110. (R)-(1-(4-fluoropheny1)-6-((3,4,5-trifluorophenyl)sulfony1)-4,4a,5,6;7,8-hexahydro-1H-pyrazolu[3,4-g]isoquilluliii-4a-y1)(pyridiu-2-yOmethaulum, Example 11R. (R)-(6-((3-chloro-4-fluorophenyl)sulfony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo [3,4-g] soqui noli n-4a-yI)(pyri di n-2-yl)methano ne, Example 11 S. (R)-34(1-(4-flu.ompheny1)-4a-(4-methylpicol inoy1)-4a,5,7,8-tetrahydro-1H-pyrazolo [3,4-g] isoquinolin-6(4H)-yl)sulfonyljbenzonitrile, Example 11T. (R)-(1-(4-fluoropherty1)-64(1-methy1-1H-pyrazol-4-yl)sulfony1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-disoquinolin-4a-y1)(4-methylpyridin-2-yOmethanone, Example 11U. (R)-(64(3,4-difluorophenypsulfony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-disoquinolin-4a-y1)(4-m.ethylpyridin-2-yOmethanone, Example fl Y. V. (R)-(1-(4-fluoropheny1)-6-((1-methyl-IH-imidazol-4-ypsulfony1)-4,4a,5,6,7,8-hex ahydro-1H-pyrazolo [3,4-g] isoquinolin-4a-y1)(4-methylpyridin-2-yl)m.ethanone, Example 11W. 044643,5-di fluorophenyl)sulfony1)-1-(4-fluoropheriy1)-4,4a,5,6,7,8-hex.abydro-

11-I-pyrazolo[3,4-g]isoquinolin-4a-y1)(4-rnethylpyridin-2-ypmethanotie, Example 11X. (R)-(1-(4-fluoropheny1)-643,4,5-trifluorophenyl)sulfony1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-g]isoquinolin-4a-y1)(4-methylpyridin-2-yl)methanone, Example 11Y. (R)-(1-(4-fluoropheny1)-643-(methylsulfony1)phenyl)sulfony1)-4,40,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-yOmethanone, Example 11Z. (R)-3-01-(4-fluoropheny1)-4a-pico linoy1-4a,5,7,8-te trahydro-1H-pyrazolo [3,4-isoquinolin-6(4H)-yl)sulfonyl)benzoic acid, Example 11A A. (R)-(1-(4-fluoropheny1)-64(3-(methoxymetbyl)phenA)sulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(ppidin-2-yl)methanone, Example 11AB. (11)-(1 -(4-fluoropheny1)-6-04-m ethy1-3,4-d ihydro-2H-pyri do[3,2-b][1,4]oxazin-7-yl)sulfony1)-4,4a,5,6,7,8-hexahydro- I H-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-yl)methanone, Example I I AC. (R)-(1-(4-fluoropheny1)-6-((2,3,4-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-lH-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-ypmethanone, Example I I AD. (R)-(I -(4-fluoropheny1)-64(6-(trifluoromethyppyri din-2-yl)sulfony1)-I 5 4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-yl)rnethanone, Example I I AE. (R)-( 1 -(4-fluoropheny1)-64(6-(trifluoromethyl)pyridin-2-yl)sulfony1)-4,4a,5,6,7,8-hexahydro- I H-pyrazolo[3,4-g] isoq uinolin-4a-y1)(4-methylpy ridin-2-yl)oie thulium, Example 11AF. (R)-(643,4-dichlorophenypsulfony1)-1-(4-fluoropheny1)-4,43,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-yOmethanone, Example 11AG. (R)-(1-(4-fluoropheny1)-64(3-(trifluoromethy1)phenyl)su1fony1)-4,4a.5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(4-methylpyridin-2-yOmethanonc, Example 11AH. (R)-(6-((1-ethyl-1H-pyrazol-4-yOsulfony1)-1-(4-fluorophcny1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-yfl(4-methylpyridin-2-yOmethanone, Example 1 I AI. (R)-(641,5-dimethy1-1H-pyrazol-4-yl)sulfony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hex ahydro-1H-pyrazolo[3,4-g] isoquinolin-4a-y1)(4-methylpyrid in-2-yl)m ethanone, Example ii Al. (R)-(1-(4-fluoropheny1)-64(1-methyl -1H-pyrazol-5-yl)sulfony1)-4,4a,5,6,7,8-hex ahydro-1H-pyrazolo[3,4-d isoquinolin-4a-y1)(4-methylpyridin-2-yl)methanone, Example ii AK. (R)-(1-(4-fluoropheny1)-64(1-methyl -1H-pyrazol-3-yl)sulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(4-methylpyridin-2-Amethanone, Example 11AL. (R)-(6-04-fluoro-3-methylphenypsulfony0-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-g]isoquinolin-4a-y1)(4-methylpyridin-2-y1)methanone, Example 11AM. (R)-(1-(4-fluoropheny1)-6-04-methyl-3,4-dihydro-2H-pyrido [3,2-b][1,4]oxazin-7-yOsulfony1)-4,4a,5,63,8-hexahydro-1H-pyrazolo [3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone, Example 1 1 AN. (R)-(6-((2,3-dihydrobenzofuran-5-yl)sulfony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hex ahydro-1H-pyraz.olo[3,4-g] isoquinolin-4a-y1)(4-methylpyridin-2-yl)methanone, Example 11 AO. (R)-54144-fluoropheny1)-4a-(4-methylpicolinoy1)-4a,5,7,8-tetrahydro- I I-1-pyrazolo [3,4-g] isoquin olin-6(4H)-yl)sulfonyI)-1-methyli ndol in-2-on e, Example 11 AP. (R)-(1-(4-fluoropheny1)-6-03-(methy Isulfonyl)phenyl)sulfony1)-4,4a,5,6,7,8-hex ahydro-1H-pyrazolo [3,4-g] isoquinolin-4a-y1)(4-methy 1pyrid in-2-yl)m.ethanone, Example I I AQ. (R)-(64(1,3-dimethy1-1H-pyrazol-4-y1)sulfony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro- I li-pyrazolo[3,4-disoquinolin-4a-y1)(4-methylpyridin-yl)methanone, Example 1 I AR.. (R)-(6-02,3-dihydrobenzo[b][1,4]dioxin-6-yOsulfony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-lli-pyrazolo[3,4-g]isoquinolin-4a-y1)(4-methylpyridin-2-y1)methanone, Exam* 11 AS. (R)-(6-((3-fluu ru-4-(tri 1111010HW thyl)pliclly 1)sulfuny1)-1 -(4- fluoroplieny1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g] isoquinoli n-4a-y1)(4-methylpyridin-yl)methanone, Example 11AT. (R)-(64(3-fluoro-4-(trifl uoromethyl)phenyl)sulfonyl)-144-fluoropheny1)-4,4a,5,6,7.8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-yOmethanone, Example 11A11. (R)-3-((4-(4-ethylpicolinoy1)- I -(4-fluoropheny1)-4a,5,7,8-tetrahydro- I H-pyrazolo [3,4-g] isoquinolin-6(4H)-yl)sulfonyl)benzonitrile, Example 1 I AV. (R)-(4-ethylpyridin-2-y1)(1-(4-fluoropheny1)-6-06-(trifluoromethyl)pyridin-2-yl)sulfony1)-4,4a,5,6,7,8-hex.ahydro-IH-pyrazolo[3,4-g]isoquinolin-4a-Amethanone, Example 11 AW. (R)-34(1-(4-fluoropheny1)-4a-(4-methylpicolinoy1)-4a,5,7,8-tetrahydro-IH-pyrazolo [3,4-g] isoquinolin-6(4H)-yl)sulfonyl)benzoic acid, Example 11 AX. (R)-(6-((3,5-dimethylisoxazol-4-yl)sulfony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo [3,4-g] soquinol in-4a-y I)(4-methy 1pyridin-2-yl)m.ethanone, Example 11AY. (R)-(64(1-ethy1-1H-pyrazol-4-y1)sulfony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-g]isoquinolin-4a-y1)(pyridin-2-yl)methanone, Example 11AZ. (R)-(1-pheny1-643-(trifluoromethyl)phenyl)sulfony1)-4,4a5,6,7,8-hexahydro-IH-pyrazolo[3,4-g]isoquinolin-4a-y1)(pyridin-2-y1)methanone, Example 11 BA. (R)-(6-((1 ,3-dimethyl- 1 H-py razol-5-yl)s ulfonyI)- 1 -(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-d isoquinolin-4a-yD(4-methylpyridin-2-yl)methanone, Example 11BB. (R)-( 1 -(4-fluoropheny1)-64(2-(trifluoromethyppyridin-4-Asid fonyI)-4,4a,5,6,7,8-hexahydro-1H-pyrazol o [3,4-d isoq n-4a-yI)(4-methylpyridin-2-yl)methanone, Example ii BC. (R)-(1-(4-fluoropheny1)-6-04-(trilluoromethyl)pyridin-2-ypsulfonyl)-4,4a,5,6,7,8-hexahydro-IFI-pyrazolo[3,4-disoquinolin-4a-y1)(4-methylpyridin-2-y1)methanone, Example I 1BD. (R)-(1-(4-fluoropheny1)-64(5-methyl-114-pyrazol-4-yl)sulfony0-4,4a,5,6,7,8-hex ahydro-1H-pyrazolo [3,4-g] soquinol in-4a-y1)(4-methylpyridin-2-yl)m ethanone, Example I 1 BE. (R)-(1-(4-fluoropheny1)-6-02-(trifluoromethyl)pyridin-4-yOsulfony1)-4,4aõ5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-yOmethanone, Example 11 BF. (R)-(6-04-chloro-3-(tlifluotomedly1)phenyl)sulfony1)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-yOmethanone, Example 11BO. (R. )-(6-((3-chloro-4-methylphenyl)sulfony1)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hex ahydro-1H-pyrazol o[3,4-g] isoqui nolin-4a-y1)(pyridin-2-yl)methanone, Example 11BH. (R)-(643,4-difluorophenypsulfony1)-1-(4-fluoropheny1)-4,4a,5.6,7,8-hexahydro-1H-pyrazolo [3,4-g] isoquino lin-4a-y1)(2-(pyrrolidin-l-yl)pyridin-4-yl)methanone, Example 11Bl. (R)-(1-(4-fluoropheny1)-64(1-methy1-1H-pyrazol-3-yl)sulfony1)-4,4a,5,6,7,8-hex ahydro-1H-pyrazolo [3,4-g] isoqui nolin-4a-y1)(4-(trilluoromethyl)pyrid in-yl)methanone, Example 11B.T. (R)-(1-(4-fluoropheny1)-6-((1-methyl-1H-pyrazol-3-yl)sulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazoloP,4-glisoquinolin-4a-y1)(pridin-2-y1)methanone, Example 11BK. (R)-(1-(4-fluoropheny1)-6-((5-methy1- I H-pyrazol-4-yl)sulfony1)-4,40,6,7,8 -hexahydro-1H-pyrazolo [3,4-g] isoqui nolin-4a-yI)(4-(trifluoromethyl)pyridin-2-yl)methanone, Example 11BL. (R)-3-41-(4-fluoropheny1)-4a-(4-(tri fluoromethyppicolinoy1)-4a,5,7,8-tetrahydro- I H-pyrazolo [3,4-g] isoquinohn-6(4H)-yl)sulfonyl)benzonitri le, Example 11BM. (R)-(1-(4-fluoropheny1)-6-((1-methyl-lH-pyrazol-5-ypsulfonyl)-4,4a,5,6,7,8-hex ahydro-1H-pyrazolo [3,4-g] i soqui nol in-4a-y1)(4-(trifl uoromethyppyri di n-2-yl)methanone, Example 11BN. (1)464(1 ,5-dimethy1-1H-pyrazol-4-yl)sulfony1)-1-(4-11uoropheny1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquin ol in-4a-y1)(4-(trifluoromethyl)pyri din-2-yl)methanone, Example I 1BO. (R)-(641H-pyrazol-4-ypsulfony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-III-pyrazolo[3,4-g]i soquinolin-4a-y1)(4-(tri fluoromethyl)pyridi n-2-yOmethan one, Example I 1BP. (R)-(1-(4-fluoropheny1)-6-41-meth y1-3-(trifl uoromethyl)-111-pyrazol-4-yl)sulfony1)-4,4a,5,6,7,8-hexahydro-111-pyrazolo[3,4-g] isoqui noli n-4a-yI)(pyri di n-2-Amethanone, Example 11BQ. (R)-(1-(4-fluoropheny1)-6-((3,4,5-tri fluorophenyl)sulfony1)-4,4a,5,6,7,8-hexahydio- 1 EI-pyl azolu[3,4-g] isoquilluliii-4a-y1)(4-(t1 Mum. uniuthyl)pyi idin-2-Amethanone, Example 11BR. (R)-(1-(4-chloropheny1)-6-((I-methyl-IH-pyrazol -3-yl)sulfony1)-4,4a,5,6,7,8-hex ahydro-1H-pyrazol o [3.4-g] i soqui nolin-4a-y1)(4-(trifluoromethyl )pyridin-2-yl)methanone, Example 11BS. (R)-(6-((1H-pyrazol-4-yl)sulfony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-g]isoquinolin-4a-y1)(pyridin-2-y1)methanone, Example 11BT. (R)-(6-((1-methy1-1H-pyrazol-3-yl)sulfony1)-1-(4-(trifluoromethyl)pheny1)-4,4a,5,6,7,8-hexahydro-IH-pyrazo1o[3,4-disoquinolin-4a-y1)(pyridin-2-Amethanone, Example 11BU. (R)-(6-((3,4-difluorophenypsulfony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-g]isoquinolin-4a-y1)(thiazol-4-ypmethanone, Example 11BV. (R )-(6-((1,2-dimethy1-1H-imi dazol-4-yi)sul fony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolop,4-0isoquinolin-4a-y1)(4-(trifluoromethyl)pyridin-2-yl)methanone, Example 11B W. (R)-(641 ,2-dimethy1-1H-imidazol-5-y1)sulfony1)-1-(4-fluoropheny1)-4,4aõ5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(4-(trifluoromethyl)pyridin-2-yOmethanone, Example 11BX. (R)-(1-(4-fluoropheny1)-6-01-methy1-1H-imidaz,o1-2-ypsulfonyl)-4,4a,5,6,7,8-hexahydro- 1 H-pyrazolo[3,4-g] isoquinolin-4a-y1)(4-(trifluoromethyl)pyridin-2-yl)methanone, Example 1 1 BY. (R)-(6-((1 -ethy1-1H-imidazol-4-yl)sulfony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(4-(triflooromethyl)pyridin-2-y1)methanone, Example 11BZ. (11)-(6-(0 -ethy1-1H-pyrazol-4-yps ulfony1)-1-(4-fluoropheny hex ahydro-IH-pyrazolo[3,4-g] isoquinolin-4a-y1)(thiazol-4-yOm ethanone, Example 11 CA. (R)-(1-(4-fluoropheny1)-6-((1-propyl-1H-pyrazol-4-yl)sulfony0-4,445,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-ypmethanone, Example I 1CB. (R)-( 1. -(4- fluo rophenyI)-6- 1-(2-methoxyethyl)-1H-pyrazol-4-yl)sulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazo1o[3,4-disoquinolin-4a-y1)(pyridin-2-yprnethanone, Example I 1 CC. (R)-(6-((3,4-diehlorophenyl)sulfony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-disoquinolin-4a-y1)(1-methyl-1H-pyrazol-4-yl)methanone, Exampls: 11 CD. (R)-(1 -(4- fluoruplieny1)-6-(( 1 -isupropy I- 1 H-py razol-4-yl)sulfoiry1)-4,4u,5,6,7,8-hexahydro-IH-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-yl)methanone, Example 110E. (R)-(1-(4-fluoropheny1)-6-((2-methyl-2H-1,2,3-triazol-4-y1)sulfony1)-4,4a,5,6,7,8-hexahydro- 1 H-pyrazolo[3,4-disoquinol in-4a-y1)(4-(tri fluor methyppyri di n-2-yl)methanone, Example 11CF. (R)-(1-(4-fluoropheny1)-6-((l -methyl-1 H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-Example ii CG. (R)-(1-(4-fluoropheny1)-641-methyl-11-1-1 ,2,3-triazol-4-yOsulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-d isoquin ol in-4a-y1)(4-(trifluoromethyl)pyri din-2-yl)methanone, Example 11CH. (R )-(642-ethy1-2H-1,2,3-triazol-4-y1)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-yl)methanone, Example 11CI. (R)-(6-((1-ethyl-IH-1,2,3-triazol-5-yl)sulfony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-g]isoquinolin-4a-y1)(pyridin-2-yl)methanone, Example 11C,E. (R)-(641-ethy1-1H-1,2,3-triazol-4-y1)sulfony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-ypmethanone, Example 1 1 CK. (R)-(6-((2-ethyl-2H- 1 ,2,3-triazol-4-yl)sulfony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-yD(4-(trifluoromethyl)pyridin-2-yl)methanone, Example 11CL. (R)-(6-((1-ethy1-11-1- ,2,3-tri azol-5-yl)sul fony1)- 1 -(4-fluoropheny1)4,41a,5,6,7,8-hex ahydro-1H-pyrazolo[3,4-g] isoquinolin-4a-y1)(4-(trifluoromethyl)pyrid in-2-yOmethanone, Example 11CM. (R)-(64(1-ethyl-IH-1,2,3-triazol-4-yl)sulfony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinol in-4a-yI)(4-(trifluoromethyl)pyri din-2-yl)methanone, Example 1CN. (R)-(I -(4-fluoropheny1)-6-((2-propyl-211-1,2,3-triazol-4-y1)sul fonyI)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-ypmethanone, Example 1CO. (R)-(I -(4-fluoropheny1)-6-((1-propyl-111-1,2,3-triazol-5-y1)sulfony1)-4,4aõ5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-yOmethanone, Example 1 1CP. (R)-(1 -(4-fluoi oplieny1)-6-(( 1 -pi upyl-1 H- 1 ,2,3-ti iitho I-4-y Ds ul fully1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g] isomiinolin-4a-y1)(pyrid in-2-34)methanone, Example 11CQ. (R. )-(1-(4-fluoropheny1)-6-((2-propy1-2H-1,2,3-triazol-4-yl)sulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinol in-4a-y1)(th azo 1-4-yl)methanone.
Example 11CR. (R)-( I -(4-fluoropheny1)-6-((1-propy1-1H-1,2.3-triazol-5-y1)sulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(thiazol-4-yl)methanone, Example 11CS. .2,3-triazol-4-yl)sulfonyl)-Example 11CT. (R)-( I -(4-fluoropheny1)-6-((2-isopropyl-2H-1,2,3-triazol-4-Asulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-yl)methanone.
Example 11CU. (R)-(1 -(4-fluoropheny1)-64(1-isopropy1-1H-1,2,3-triazol-5-y1)sulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-Amethanone.
Example 11 CV. (R)-(1-(4-fluoropheny1)-6-((1-isopropyl-1FI-1,2,3-triazol-4-y1)sulfonyl)-4,4a,5,6,7,8-hexahydro-1 H-pyrazolop,4-gi i soquin al in-4a-yI)(pyridin-2-yl)methanone, Example 11CW. (R)-(641-ethyl-1H-pyrazol-5-ypsulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-g]isoquinolin-4a-y1)(thiazol-4-yOmethanone, Example 11CX. (R)-(1-(4-fluoropheny1)-6-((1-propyl-1H-pyrazol-4-y1)sulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo [3,4-g] isoquinolin-4a-y1)(4-(trifluoromethyl)pyridin-2-yl)methanone, Example 11CY. (R)-(1-(4-fluoropheny1)-6-((1-methy1-111-pyrazol-4-yl)sulfony1)-4,4a,5,6,7,8-hex ahydro-1H-pyrazolo [3,4-g] i soqui nolin-4a-y1)(thiazol-4-yl)m ethanone, Example 11 CZ. (R)-( 1 -(4-fluoropheny1)-64( 1 -propyl - Ill-pyrazol-4-yl)sulfony1)-4,4a,5,6,7,8-hex ahydro-1H-pyrazolo[3,4-g] isoquinolin-4a-y1)(thiazol-4-yl)m.ethanone, Example 12. (R)-(1-(4-fluoropheny1)-64(3-(trifluoromethyl)phenyl)sulfony1)-4,4a,5,6,7,8-hex ahydro-1H-pyrazolo[3,4-g] isoquinolin-4a-y1)(thiazol-2-yl)m.ethanone, Example I 2A. (R)-(1-(4-fluoropheny1)-6-(m-tolylsulfony1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo [3,4-g] isoquin olin-4a-y1)(thiazol-2-yl)methanone, Example I 2B. (R)-(1 -(4-fluoropheny1)-6-((3-methoxyphenypsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(thiazol-2-yl)methanone, Example I 2C. (R)-(6-((3-fluoro-4-methylphenyl)sulfonyt)-1-(4-fluorophen y1)-4,40,6,7,8-hexahydro-1H-pyrazolo [3,4-g] isoqui nolin-4a-y1)(thiazol-2-yOmethanone, Example 12D. (R)-(1-(4-fluutupheny1)-6-(pholy ls ulfu lly1)-4,4d,5,6,7,8-litaithy duo- 1 H-pyrazolo [3,4-g] isoquinolin-4a-y1)(thiazol-2-yl)methanone, Example 12E. (R)-(6-((3-chlorophenypsulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-IH -pyrazolo [3,4-g] isoqui n ol n-4a-y1)(thiazol-2-Amethanone, Example 12F. (12)-(1-(4-fluoropheny1)-6-(m-tolyisulfony1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo [3,4-g] isoquinolin-4a-y1)(5-methylpyridin-2-yl)methanone, Example 12G. (R)-(1-(4-fluoropheny1)-6-(m-tolylsulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo [3,4-g] isoquinolin-4a-y1)(4-methylpyridin-2-Amethanone, Example 1211. (R)-(1-(4-fluoropheny1)-6-(m-tolylsulfony1)-4,4a,5,6,7,8-hexahydro-111-pyrazolo [3,4-g] isoquinolin-4a-yI)(6-methylpyri din-2-yl)meth anone, Example 121. (R)-(64(4-fluoro-3-(trifluoromethyl)phenyl)sulfony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(thiazol-2-yl)m.ethanone, Example 12J. (R)-(1-(4-fluoropheny1)-6-((3,4,5-tri fluorophenyl)sulfony1)-4,4a,5,6,7,8-hexahydro-1 H-pyrazolo [3,4-g] isoque nolin-4a-y1)(thiazol -2-yl)methanone, Example 12K. (R)-(64(3-fluoro-4-(trifluoromethyl)phenyl)sulfony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(thiaw1-2-yl)methanone, Example 12L. (R)-(1-(4-fluoropheny1)-643-(trifluoromethyl)phenypsulfony1)-4,40 ,6,7,8-hexahydro-1H-pyrazolo [3,4-g] isoquinolin-4a-y1)(5-methy Ithiazol-2-yl)methanone, Example 12M. (R)-(1-(4-fluoropheny1)-64(3-(trifluoromethypphenyl)sulfony1)-44a,5,6,7,8-hexahydro-1H-pyrazolo [3,4-g] isoquinolin-4a-y1)(4-methylthiazol-2-yl)methanone, Example I 2N. (R)-(6-((3,4-dich1oropheny1)su1fony1)-1-(4-fl uorophenyI)-4,4aõ5,6,7,8-hex ahydro-I H-pyrazol.o[3,41-disoquinolin-4a-y1)(thiazol-2-yl)methanone, Example 120. (R)-(64(3,4-di ch lorophenyl)sulfony1)-1-(4-fl uoropheny1)-4,4a,5,6,7,8-hexahydro-I H-pyrazolo[3,4-disoquinolin-4a-y1)(5-methylthiazol-2-y1.)methanone, Example 12P. (R)-(64(3,4-di fluorophenyl)sulfony1)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexab ydro-I H-pyrazolo[3,4-disoquino1in-4a-y1)(thiazo1-2-yl)methanone, Example 12Q. (R)-(6((3,4-difluorophenyl)sulfony1)- I -(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-disoquinolin-4a-y1)(5-methylthiazol-2-yl)methanone, Example 12R.. (R)-(6-(4-chloro-3-fluorophenyl)sulfony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-111-pyrazoloP,4-disoquinolin-4a-y1)(5-methylthiazol-2-yOmethanone, Example 12S. (R)-(1-(4-fluoropheny1)-6-((1-methyl-1H-pyrazol-3-yl)sul fonyI)-4,4a,5,6,7,8-hexahy duo- 1 EI-pyld.ZOlo[3,4-g]isoquilluliii-4a-y1)(5-inelliyithiaLul-2-y1)Inethanuu Example 121. (R)-(1-(4-fluoropheny1)-6-((1-methyl-IH-pyrazol-4-yl)sulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(5-methylthiazol-2-yl)methanone, Example 12U. (R)-(6-(( I ,3-dimethy1-11-1-pyrazol-5-yl)sulfony1)-1-(4-flueropheny1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(5-methylthiazol-2-yOmethanone, Example 12V. (R)-(1-(4-fluoropheny1)-641-methyl-1H-pyrazol-5-ypsulfony1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-disoquinolin-4a-yD(5-methylthiazol-2-yOmethanone, Example 12W. (R)-(641-ethy1-1H-pyrazol-5-yOsulfony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hex ahydro-IH-pyrazolo [3,4-g] isoquinolin-4a-y1)(thiazol-2-yl)m.ethanone, Example 12X. (R)-(6-((1-ethy1-1H-pyrazol-4-yl)sulfony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-g]isoquinolin-4a-y1)(thiazol-2-yl)m.ethanone, Example 12Y, (R)-(1-(4-fluoropheny1)-6-((1. -propy1-1H-pyrazol-4-y1.)sulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-y1)(thiazol-2-yl)m.ethanone, Example 13. (R)-(1-(4-fluoropheny1)-6-tosyl-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-isoquinolin-4a-y1)(1-methyl-1H-imidazol-2-y1)methanone, Example 13A. (R)-(1-(4-fluoropheny1)-6-(m-tolylsulfony1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo [3,4-g] isoquinolin-4a-y1)(1-methy1-1H-imidazol-2-yOmethanone , Example 14. (R)-3-01-(4-fluoropheny1)-4a-picolinoy1-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-disoquinolin-6(4H)-yl)sulfony1)-N,N-dimethylbenzamide, Example 15. (R)-(64( I -ethyl-1H-pyTazol-4-yl)sulfony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(4-(trifluoromethyl)pyridin-2-yl)methanone, Example 15A, (R)-pyridin-2-y1(1-(pyridin-3-y1)-64(3-(trifluorom.ethyl)phcnyl)sulfony1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-0isoquinolin-4a-y1)methanone, Example 15B. (R)-(6-((3,4-dichlorophenyl)sulfony1)-1-pheny1-4,4a,5,6õ7,8-hexahydro-114-pyrazolo[3,4-disoquino1in-4a-y1)(pyridin-2-yl)methanone, Example 15C. (R)-(64(3,4-dichlorophenyl)sulfony1)-1-(3,4-difluoropheny1)-4,4a,5,6,7,8-hex ahydro-1H-pyrazolo[3,4-g] isoquinolin-4a-y1)(pyridin-2-yl)methanone, Example I5D. (R)-(6-((3,5-difluoro-4-methoxyphenyl)sulfonyt)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-y1)methanone, Example 16. (R)-(6-06-(dimethy lamino)py ulfouy 1)- 1 -(4-fluorupheity1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-y1)methanone, Example 17. (R)-5-((1-(4-fluoropheny1)-4a-picolinoy1-4a,5,7,8-tetrahydro-1H-pyrazo 10[3,4-disoquinol in-6(4H)-y 1)sulfony1)-1-methylpyridin-2( 1 H)-one, Example 18. (R)-(1-(4-fluoropheny1)-6-((1-methy1-1H-pyrazol-4-Asulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(4-(trifluoromethyl)pyridin-2-y1)methanone, Example 19. (R)-(6-((3,4-dichlorophenyl)sulfony1)-1-(4-fluorophenyl)-4,4aõ5,6,7,8-hexahydro-IH-pyrazolo[3,4-disoquinolin-4a-y1)(thiazol-4-yOmethanorie, or salts and isomers thereof.
[00651 In some embodiments, the compound of formula I can be (R)-(1-(4-fluoropheny1)-6-((2-methyl-2H-1,2,3-triazol-4-yOsul fony1)-4,4a,5,6,7õ8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(thiazol-4-yl)methanone, (R)-(1-(4- fluoropheny1)-6-01-methy 1-1H-1,2,3- triazo1-5-yl)sulfony1)-4,4a,5,6,7,8- hexahydro-1H-pyrazolo[3,4-g] isoquino lin-4a-y1)(thiazol-4-yl)methanone, or (R)-(1-(4-fluoropheny1)-6-((1 -methy1-1H-1,2,3-triazol-4-y1)sulfony1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-g]isoquinolin-4a-y1)(thiazol-4-yOmethanone.
[00661 In some embodiments, the compound of formula I can be (R)-(1-(4-fluoropheny1)-6-((2-methyl-2H-1,2,3-triazol-4-yOsulfony1)-4,4a,5,6,7,8-hexabydro-IH-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-yl)methanone, (R)-(1-(4-fluoropheny1)-6-((1 -methyl-1H-1,2,3-triazol-5-yl)sulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g] isoquinol in-4a-y1)(pyri din-2-yl)methanone, or (R.)-(1-(4-fluoropheny1)-6-((1-methyl-IH-1,2,3-triazol-4-y1)sulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g] i soquinolin-41-y1)(pyri din-2-yl)meth [00671 In some embodiments, the compound of formula I can be (R)-(1 -(4-fluoropheny1)-6-((2-propy1-2H-1,2,3-triazol-4-yl)sulfony1)-4,4a,5,6,7,8-h ex ahydro-1H-pyrazolo [3,4-g] isoquinolin-4 a-y1)(4-(tri fluorometh yl)pyridi n-2-yl)methan one, (R)-(1-(4-fluoropheny1)-6-((1-propyl-lH-1,2,3-triazol-5-y1)sulfonyl)-4,4a,5,6,7,8-h ex ahydro-1H-pyrazolo [3,4-g] isoy uinolin-4a-y1)(4-(tri fl uorometb yl)pyridin-2-yl)methanon e, or (R)-(1-(4-fluompheny1)-6-01-propyl-1 H-1 ,2 pyrazolo [3,4-g] isoquinol in-4a-y1)(4-(tri fluoromethyppyridin-2-yOmethanone.
100681 In some embodiments, the compound of formula I can be (1)41 -(4-fluoropheny1)-6-((2-mothyl-214-1,2,3-trio.zol-4-y Osulfony1)-4,4a,5 ,6,7,8-hcxab ydro-H-pyrazolo[3,4-g] soquino I in-4a-y1)(thiazol-2-yl)methanone, (R)-(1 -(4-fluoropheny1)-6-((1-methy 1-1 H-1,2,3-triazol-5-yl)sullony1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-g]isoquinolin-4a-y1)(thiazol-2-yl)methanone, or (R)-(1-(4-fluoropheny1)-6-((1 -methyl-1H-1,2,3-triazol-4-yl)sulfony1)-4,4a,5,6,7,8- hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-y1)(thiazol-2-yl)methanone.
190691 In some embodiments, the compound of formula I can be (R)-(1-(4-fluoropheny1)-6-((2-propyl-2H-1,2,3-triazol-4-yl)sulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo [3,4-g] soquinol i n-4a-y1)(thiazol-2-yl)methanone, (R)-(1-(4-fluoropheny1)-6-((1-propyl-IH-1,2,3-triazol-5-y1)sulfony1)-4,4a,5,6,7,8-hexahydro-11-1-pyrazolo [3,4-g] isoquinolin-4a-y1)(thiazol-2-yl)mcthanone, or (R)-(1-(4-fluoropheny1)-6-((1-propyl-IH-1,2,3-triazol-4-y1)sulfony1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-g]isoquinolin-4a-y1)(thiazol-2-yl)methanone.
[00701 In some embodiments, the compound of formula I can be (R)-(1-(4-fluoropheny1)-6-04-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexa hydro-1H-pyrazolo [3,4-g] isoquinolin-4a-y1)(pyridin-2-yOmethanone, (R)-(1-(4-fluoropheny1)-6-04-(trifluoromethyl)phenyl)sulfony1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo [3,4-g] isoquinolin-4a-y1)(thiazol-2-yl)methanone, (R)-(64(3,4-difluorophenypsulfony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-pyrazolo [3,4-g] isoquinolin-4a-y1)(pyridin-2-yl)methanone, (R)-(6((3,4-dichlorophenyl)sulfony1)-1-(4-fluoropbeny1)-4,4a,5,6,7,8-hexahydro-I H-pyrazolo [3,4-g] isoquinolin-4a-y1)(pyridin-2 -yl)nacthanono, (R)-(1-(4-fluorophenyl)-6-((1-methyl -1H-pyrazol-4-yl)sulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo [3,4-g] isoquin olin-4a-y1)(4-(trifluorom.ethyppyridin-2-y1)methanone, (R)-(6((3,4-dichlorophenyl)sul fony1)-1-(4-fluoropbeny1)-4,4a,5,6,7,8-hex ahydro-1H-pyrazolo [3,4-g] isoquin olin-4a-y1)(thiazol-2-yl)methanone, (R)-(6-((3,4-dichlorophenyl)sulfony1)-1-(4-fl uoropbeny1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo [3,4-g] isoquin olin-4a-y1)(5-methylthiazol-2-yl)m.ethanone, (R)-(6-03-fluoro-4-(trifluorometbyl)pheny1)sulfo ny1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo [3,4-g] soqui nol in-4a-y I)(pyri di n-2-y1 )methanone , (R)-(1-(4-fluoropheny1)-6-((1-methy1-1H-pyrazol-3-yl)sulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo [3,4-0 isoquinolin-4a-y1)(4-(tritluoromethyl)pyridin-2-yl)methanonc, (R)-(1-(4-fluoropheny1)-6-((1-methyl-IH-pyrazol-5-y1)sulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo [3,4-g] isoquinolin-4a-yI)(4-(tri fluoromethyppyridin-2-yl)methanone, (R)-(6-(( 1 -ethyl-1 H-pymzol-5-yl)sulfonyl)- 1 -(4-fluoropheny1)-4,4 a.,5,6,7,8-hexahydro- I H-pyrazolo [3,4-g] isoquinolin-4a-y1)(4-(tri fluoromethyppyridin-2-yl)methanone, or (R)-(6-((34-dich1orophenyl)sulfony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-pyrazolo [3,4-g] isoquinolin-4a-y1)(thiazol-4-y1)methanone.

I00711 The compounds of the present invention can also include compounds of formula 11:
R1 OH 0I., 0 N '(CF12)n = (R2)1_4 N' wherein RI, R2, R3, ring J and subscript n are as described above.
100721 When R3 of formula II is 4-F.-phenyl, the compounds of formula Il can have the following structure:

õ
N I N,s'ICH2),¨(14 Nfl - N" '(CH2)õ =
(R2)1.4 r:f=-"1",-I

or F
Alternatively, the compounds of formula 11 can have the following structure:
Ri OH 0õ0 01 OH 0 0 m N 111; (R2)1-4 N4-111.. L21)-(R2)1_4 or [00731 In some embodiments, the compound of formula II can be Intermediate 3. (R)-(1-(4-fluoropheny1)-64(4-(trifluoromethyl)phenypsulfonyl)-4,40,6,7,8-hexahydro-lH-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-y1)-(RIS)-methanol, Intermediate 4. (R)-(1-(4-fluoropheny1)-6-44-(trifluoromethyl)phenyl)sulfony1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-disoquinolin-4a-ylApyridin-3-yl)-(RIS)-methanol, Intermediate 5. (R)-(1-(4-fluoropheny1)-6-44-(trifluoromethyl)phenyl)sulfony1)-4,40,6,7,8-15 hexahydro-1H-pyrazolo [3,4-g] isoquinolin-4a-y1)(1-methy1-1H-imidazol-2-y1)-(M)-methanol, Intermediate 6. (R)-(1 -(4-fluoropheny1)-64(4-(trifluoromethyl)phenyl)sulfony1)-4õ40,6,7,8-hexahydro-1H-pyrazolo [3,4-g] isoquinolin-4a-yI)(th iazol-2-y1)-(111S)-methanol, Intermediate 7. (R)-(1-(4-fluoropheny1)-64(4-(trifluoromethyl)phenyl)sulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(oxazol-4-y1)-(R/S)-methanol, Intermediate 8. (R)-( I -(4-fluoropheny1)-64(4-(trifluoromethyl)phenyl)sulfony1)-4,40,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(fitran-2-y1)-(RiS)-methanol, Intermediate 9. (R)-(1-(4-fluoropheny1)-6-44-(trifluoromethypphenyl)sul fonyI)-4,4a,5,6,7,8-hexah ydro-1H-pyrazolo [3,4-g] isoqu inolin-4a-y1)(thiophen-2-y1)-(R/S)-methanol, Intermediate 15. (.R)-(l -(4-fluoropheny1)-6-44-(trill uoromethyl)phenyl)sul fonyI)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g] isoquinolin-4a-y1)(5-methy1-1,3,4-oxadi azol-2-y1)-(R/S)-methanol, Intermediate 16. (R)-(1-(4-fluoropheny1)-6-44-(trifluoromethypphenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(oxazol-2-y1)-(RIS)-methanol, Intermediate 17. (R)-( I -(4-fluorophenyI)-6-(m-tolylsulfony1)-4,4a,5,6,7,8-hexahydro-IH-pyrazo1o[3,4-glisoquinolin-4a-y1)(oxazol-2-y1)-(111S)-methano1, Intermediate 18. (R)-(64(3,5-difluorophenyl)sulfony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-d isoquinolin-4a-y I)(4-methoxypyridin-2-y1)-(R/S)-tIntaul, Intermediate 19. (R)-(4-ethylpyridin-2-y1)(1-(4-fluoropheny1)-6-((3,4,5-trifluorophenyl)sulfony1)-4,4a,5,6,7,8-hexahydro-IH -pyrazolo[3,4-g] isoqui nolin-4a-yI)-(R/S)-methano 1, Intermediate 20. (R)-( I -(4-fluoropheny1)-64(3,4,5-trifluorophenyl)sulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g] isoqu ino lin-4a-y1)(4-methoxypyridin-2-y1)-(R/S)-methanol, or Intermediate 62. (R)-( I -(4-fluorophenyI)-6-(m-tolylsulfony1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo [3,4-g] isoquin olin-4a-yI)(pyrimi din-2-y1)-(R/S)-methanol.

Compounds of Formula 1.1 %Ne "IsCH2)n_ei (R2)1.4 Ns Intermediate RI RI" Ring J R2 R3 Compound 3 pyridin-2-y1 phenyl 4-CF3 0 4-F-phenyl 4 pyridin-3-y1 phenyl 4-CF 3 0 4-F-phenyl 1-Me phenyl 4-CI- 3 0 4-F-phenyl 2-y1 6 thiazol-2-y1 phenyl 4-CF3 0 4-F-phenyl 7 exaz.o1-4-y1 phenyl 4-CF3 0 4-F-phenyl 8 faran-2-y1 .phenyl 4-CF3 0 4-F-phenyl 9 thiophen-2-y1 phenyl I 4-CF3 0 4-F.-phenyl 1,3,4-5-Me phenyl 4-CF3 0 4-F-phenyl mold invol-,-y1 16 oxazol -2-y1 phenyl 4-CF? 0 4-F-phenyl 17 exazol-2-y1 phenyl I 3-Me 0 4-F-phenyl 18 pyridin-2-y1 4-0Me phenyl 3,5-d noro 0 4-F-phenyl 19 pyridin-2-y1 4-Et phenyl 3,4,5-Million) 0 4-F-phenyl pyridin-2-y1 4-0Me phenyl 3,4,5-trifluore 0 4-F-phenyl 62 pyrimidin-2-y1 phenyl 3-Me 0 4-F-phenyl 100741 The compounds of the present invention can also he the salts and isomers thereof. In 5 some embodiments, the compounds of the present invention include the salt forms thereof.
Examples of applicable salt forms include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumaratcs, tartrates (e.g. (-0-tartrates, (-)-tartrates or mixtures thereof including racemic mixtures), succinates, benzoates and salts with amino acids such as glutamic acid. These salts may be prepared by methods known to those 10 skilled in art. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from organic acids like acetic, propionic, isobutyric, maleic, =Ionic, benzoic, succinic, suberic, furnaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonie, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunorie acids and the like (see, for example, Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain basic acidic functionalities that allow the compounds to be converted into base addition salts. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985.
[0075] The neutral forms of the compounds arc preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.
[0076] Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
[0077] Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present invention. The compounds of the present invention do not include those which are known in art to be too unstable to synthesize and/or isolate.
The present invention is meant to include compounds in racemic and optically pure forms.
Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.

CA 287'2260 2019-05-10 [00781 Isomers include compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.
100791 It will be apparent to one skilled in the art that certain compounds of this invention may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the invention. Tautomer refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.
100801 Unless otherwise stated, structures depicted herein are also meant to include all stereochernical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention.
100811 Unless otherwise stated, the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds of the present invention may be radio labeled with radioactive isotopes, such as for example deuterium (2H), tritium (3H), iodine-125 (1251), carbon-13 (13C), or carbon-14 (14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.
100821 In addition to salt forms, the present invention provides compounds, which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with. a suitable enzyme or chemical reagent.
[00831 The compounds of the invention can be synthesized by a variety of methods known to one of skill in the art (see Comprehensive Organic Transformations Richard C.
Larock, 1989) or by an appropriate combination of generally well known synthetic methods.
Techniques useful in synthesizing the compounds of the invention are both readily apparent and accessible to those of skill in the relevant art. The discussion below is offered to illustrate certain of the diverse methods available for use in assembling the compounds of the invention.
However, the discussion is not intended to define the scope of reactions or reaction sequences that are useful in preparing the compounds of the present invention. One of skill in the art will appreciate that other methods of making the compounds are useful in the present invention. Although some compounds in Figure 1, Figure 2, and Table 1 may indicate relative stereochemistry, the compounds may exist as a racemic mixture or as either enantiomer.
[0084] Compounds of the present invention can be prepared as shown in figure 1. Starting materials can be obtained from commercial sources, by employing known synthetic methods, and by employing methods described in U.S. Patent No. 7,928,237. Esters I are converted to ketones IV by reaction with an appropriate organometallic reagent such as a Grignard reagent, an organolithium reagent, an organoboron reagent, an organocerium reagent or an organozinc reagent in a solvent such as ether or tetrahydrofuran, or a similar aprotic solvent.
Ketones of formula IV are also prepared by reaction of an aldehyde of formula II with an appropriate organometallic reagent followed by oxidation of the resultant alcohols of formula III with a suitable oxidizing agent such as the Dess-Martin periodindane reagent in an inert solvent such as dichloromethane. The tert-butoxycarbonyl protecting group is removed from IV by treatment with an acid, such as HCI, HBr, trifluoroacetic acid, p-toluenesulfonic acid or methanesulfonic acid, preferably HCI or trifluoroacetic acid, optionally in a solvent such as dioxane, ethanol or tetrahydrofuran, preferably dioxane, either under anhydrous or aqueous conditions. Amines V are converted to the compounds of formula (1) by treatment with an appropriate substituted sulfonyl halide, such as the sulfonyl chloride VI, in an inert solvent such as dichloromethane, toluene or tetrahydrofuran, preferably dichloromethane, in the presence of a base such as /V,N-di-isopropylethylamine or triethylamine. It may be convenient to carry out the sulfonylation reaction in situ, without isolation of the amine V.
Compounds of formula (1) can also be prepared from amines of formula V in a two-step sequence beginning with reaction of amines V with a halo-substituted sulfonyl chloride, VII, to afford a halo-substituted sulfonamide derivative exemplified by VIII (in which X represents a halogen). The halogen substituent X can be converted in a substituent R2 by any standard method known to those skilled in the art. For example, if R2 represents an amino substituent NR'R"
(in which NR'R" can be either an acyclic or cyclic amine), this can be introduced by treating a compound of formula VIII
with an amine HNR'R" in an inert solvent, such as tetrahydrofuran, toluene or IV,Ar-dimethylformamide, in the presence of a palladium catalyst (e.g.
BINAP/1'd2(dba)3) and a base (e.g. sodium or potassium tert-butoxide), optionally under microwave conditions, to afford compounds of formula (1). Alternatively, if X represents a fluorine or chlorine and R2 represents an amino substituent NR'R", R2 may be introduced by direct nucleophilic displacement of X.
.. This may be accomplished using any standard method known to those skilled in the art, such as by reacting a compound of formula VIII with an amine, optionally at elevated temperature, optionally under microwave conditions, optionally in an appropriate solvent such as acetonitrile or N-methylpyrrolidine.
100851 Alternatively, compounds of formula (1) arc prepared as shown Figure 2.
The tert-butoxycarbonyl protecting group is removed from I by treatment with an acid, such as HC1, HBr, trifluoroacetic acid, p-toluenesulfonic acid or methanesulfonic acid, preferably HC1 or trifluoroacetic acid, optionally in a solvent such as dioxarie, ethanol or tetrahydrofuran, preferably dioxane, either under anhydrous or aqueous conditions. Amines IX
are converted to the sulfonamides of formula X as described for the conversion of amines of formula V into sulfonamides of formula (I). The ester group in compounds of formula X is converted to an aldehyde of formula XI by using a reducing agent such as DIBAL-H, LiA1H4 or RED-AL, preferably DIBAL-H in an inert solvent such as dichloromethane, tetrahydrofuran, benzene or toluene, preferably dichloromethane. It may be convenient to convert X into XI
using a two-step process involving reduction of the ester to an alcohol and subsequent oxidation of the alcohol to .. an aldehyde of formula XI. The oxidation can be carried out using any suitable procedure, such as the Swern reaction, or an oxidizing reagent such as the Dess-Martin periodindane reagent in a suitable solvent, such as dichloromethane. Aldehydes of formula XI are converted into alcohols of formula X11 using a suitable organometallic reagent, such as a Grignard reagent, an organolithium reagent, an organoboron reagent, an organocerium reagent or an organozinc reagent. Alcohols of formula XII are converted into ketones of formula (1) by oxidation. Suitable oxidation conditions include the Swem reaction and the use of the Dess-Martin periodinane reagent. Alternatively, esters of formula X are converted directly to ketones of formula (1) using an appropriate organometallic reagent.

IV. Pharmaceutical Compositions [00861 In some embodiments, the present invention provides a pharmaceutical composition including a pharmaceutically acceptable excipient and a compound of the present invention. In some embodiments, the composition also includes an anti-inflammatory glucocorticosteroid.
Anti-Inflammatory Glucocorticosteroids 100871 Anti-inflammatory glucocorticosteroids suitable for use with the present invention include those glucocorticosteroids that bind GR and include, but are not limited to, alclometasone, alclometasone dipropioate, beclometasone, beclometasone dipropionate, betamethasone, betamethasone butyrate proprionate, betamethasone dipropionate, betamethasone valerate, budesonide, ciclesonide, clobetasol, clobetasol propionate, clocortolone, clocortolone pivalate, cortexolone, cortisol, cottisporin, cortivazol, deflazacort, deprodone, deprodone propionate, desonide, dexamethasone, dexamethasone acetate, dexamethasone cipecilate, dexamethasone palmitate, difluprednate, fludroxycortide, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortolone, fluorometholone, fluticasone, fluticasone propionate, fluticasone furoate, halcinonide, halometasone, halopredone, halopredone acetate, hydrocortisone, hydrocortisone 17-butyrate, hydrocortisone aceponatc, hydrocortisone acetate, hydrocortisone probutate, hydrocortisone sodium succinate, loteprednol, loteprednol etabonate, meprednisone, methylprednisolone, methylprednisolone aceponate, methylprednisolone suleptanate, mometasone, mometasone furoate, naflocort, 19-nordeoxycorticosterone, 19-norprogesterone, otobiotic, oxazacort, paramethasone, prednicarbate, prednisolone, prednisolone farnesylate, prednisone, prednisone sodium phosphate, prednylidene, proctosedyl, rimexolone, tobradex, triamcinolone, tTiamcinolone hexacetonide, trimexolone, ulobetasol, ulobetasol propionate, 1 113-(4-dimethylamincethoxyphenyl )-17a-propyny1-17P-hydroxy-4,9estradien-3-one (RU009), 1713-hydroxy- I 7a-19-(4-methylphenyl)androsta-4,9(11)-dien-3-one (RU044), and the salt and esters forms thereof.
[00881 Additional anti-inflammatory glucocorticosteroids suitable for use with the present invention include, but are not limited to, a naturally occurring or synthetic steroid glucocorticoid which can be derived from cholesterol and is characterized by a hydrogenated cyclopentanoperhydrophenanthrene ring system. Suitable glucocorticosteroids also include, but are not limited to, 11-alpha,17-alpha,21-trihydroxypregn-4-ene-3,20-dione; 11-beta,16-alpha,17,21-tetrahydroxypregn-4-ene-3,20-dione; 11-beta,16-alpha,17,21-tetrahydroxypregn-1,4-diene-3,20-dione; 11-beta,17-alpha,21-trihydroxy-6-alpha-methylpregn-4-ene-3,20-dione; 11-dehydrocorticosterone; 11-deoxycortisol; 11-hydroxy-1,4-androstadiene-3,17-dione; 11-ketotestosterone; 14-hydroxyandrost-4-ene-3,6,17-trione; 15,17-dihydroxyprogesterone; 16-methylhydrocortisone; 17,21-dihydroxy-16-alpha-methylpregna-1,4,9(11)-triene-3,20-dione; 17-alpha-hydroxypregn-4-ene-3,20-dione; I 7-alpha-hydroxypregnenolone; 17-hydroxy-16-beta-methy1-5-beta-pregn-9(1 I)-ene-3,20-dione; 17-hydroxy-4,6,8(I4)-pregnatriene-3,20-clione; 17-hydroxypregna-4,9(11)-diene-3,20-dione; 18-hydroxycorticosterone; 18-hydroxycortisone; 18-oxocortisol; 21-acctoxypregnenolonc; 21-dcoxyaldosteronc; 21-deoxycortisone; 2-deoxyecdysone; 2-methylcortisone; 3-dehydroecdysone; 4-pregnene-17-alpha,20-beta, 21-trio1-3,11-dione; 6,17,20-trihydroxypregn-4-ene-3-one; 6-alpha-hydroxycortisol; 6-alphafluoroprednisolone; 6-alpha-methylprednisolone; 6-alpha-methylprednisolone-21-acetate;
6-alpha-methylprednisolone 21-hemisuccinate sodium salt, 6-betahydroxy cortisol, 6-alpha, 9-alpha-difluoroprednisolone 21-acetate 17-butyrate, 6-hydroxycorticosterone; 6-hydroxydexamethasone; 6-hydroxyprednisolone; 9-fluorocortisone; alelomethasone dipropionate; algestone; alphaderm; amadinone; amcinonide; anagestone;
androstenedione;
anecortave acetate; beclomethasone; beclontediasone dipropionate;
betatnethasone 1.7-valerate;
betamethasone sodium acetate; betamethasone sodium phosphate; betamethasone valerate;
bolasterone; budesonide; calusterone; chlormadinone; chloroprednisone;
chloroprednisone acetate; cholesterol; ciclesonide; clobetasol; clohetasol propionate;
clobetasone; clocortolone;
clocortolone pivalate; clogestone; cloprednol; corticosterone; cortisol;
cortisol acetate; cortisol butyrate; cortisol cypionatc; cortisol octanoatc; cortisol sodium phosphate;
cortisol sodium succinate; cortisol valerate; cortisone; cortisone acetate; cortivazol;
cortodoxonc; daturaolonc;
deflazacort, 21-deoxycortisol, dehydroepiandrosterone; delmadinone;
deoxycorticosterone;
deprodone; descinolone; desonide; desoximethasone; dexafen; dexamethasone;
dexamethasone 21-acetate; dexamethasone acetate; dexamethasone sodium phosphate;
dichlorisone; diflorasone;
diflorasone diacetate; diflucortolone; difluprednate; dihydroelatericin a;
domoprednate;
doxibetasol; ecdysone; ecdysterone; emoxolone; endrysone; enoxolone;
fluazacort; flucinolone;
flucloronide; fludrocortisone; fludrocortisone acetate; flugestone;
flumethasone; flumethasone pivalate; flumoxonide; flunisolide; fluocinolone; fluocinolone acetonide;
fluocinonide; fluocortin butyl; 9-fluorocortisone; fluocottolone; fluorohydroxyandrostenedione;
fluorometholone;
fluorometholone acetate; fluoxymesterone; fluperolone acetate; fluprednidene;
fluprednisolone;
flurandrenolide; fluticasone; fluticasone propionate; fonnebolone; fonnestane;
fonnocortal;
gestonorone; glyderinine; halcinonide; halobetasol propionate; halometasone;
halopredone;
haloprogestcronc; hydrocortamate; hydrocortiosone cypionatc; hydrocortisone;
hydrocortisone;
21-butyrate; hydrocortisone aceponate; hydrocortisone acetate; hydrocortisone buteprate;
hydrocortisone butyrate; hydrocortisone cypionate; hydrocortisone hemisuccinate;
hydrocortisone probutate; hydrocortisone sodium phosphate; hydrocortisone sodium succinate;
hydrocortisone valerate; hydroxyprogesterone; inokosterone; isoflupredone;
isoflupredone acetate; isoprednidene; loteprednol etabonate; meclorisone; m.ecortolon;
medrogestone;
medroxyprogesterone; medrysone; megestrol; megestrol acetate; melengestrol;
meprednisone;
methandrostenolone; metbylprednisolone; methylprednisolone aceponate;
methylprednisolone acetate; methylprednisolone hemisuccinate; methylprednisolone sodium succinate;
methyltestosterone; metribolone; mometasone; mometasone furoate; mometasone furoate monohydrate; nisone; nom.egestrol; norgestom.et; norvinisterone; oxymesterone;
paramethasone;
paramethasone acetate; ponasterone; prednicarbate; prednisolam.ate;
prednisolone; prednisolone 21-diethylaminoacetate; prednisolone 21-hemisuccinate; prednisolone acetate;
prednisolone famesylate; prednisolone hemisuccinate; prednisolone-21 (beta-D-glucuronide);
prednisolone metasulphobenzoate; prednisolone sodium phosphate; prednisolone steaglate;
prednisolone tebutate; prednisolone tetrahydrophthalate; prednisone; prednival;
prednylidene; pregnenolone;
pmeinonide; tralonide; progesterone; promegestone; rhapontisterone;
rimexolone; roxibolone;
rubrosterone; stizophyllin; tixocortol; topterone; triamcinolone;
triamcinolone acetonide;
triamcinolone acetonide 21-palmitate; triamcinolone benetonide; trianicino lone diacetate;
triamcinolone hexacetonide; trimegestone; turkesterone; and wortmannin.
100891 Additional anti-inflammatory glucocorticosteroids suitable for use with the present invention include, but are not limited to, alclometasone, beclometasone, betamethasone, budesonide, ciclesonide, clobetasol, clocortolone, cortexolone, cortisol, cortisporin, cortivazol, deflazacort, deprodone, desonide, dexamethasone, difluprednate, fludroxycortide, flunisolide, fluocinolone, fluocinonide, fluocortolone, fluorometholone, fluticasone, halcinonide, halometasone, halopredone, hydrocortisone, loteprednol, meprednisone, methylprednisolone, mometasone, naflocort, 19-nordeoxycorticosterone, 19-norprogesterone, otobiotic, oxazacort, paramethasone, prednicarbate, prednisolone, prednisone, prednylidene, proctosedyl, rimexolone, tobradex, triamcino lone, trimexolone, ulobetasol, 1113-(4-dimethylaminoethoxypheny1)-17a-propyny1-17 3 -hydroxy-4,9estradien-3-one (RU009), and 17[3-hydroxy-17a-19-(4-methylphenyl)androsta-4,9(11)-dien-3-one (RU044).
[00901 The anti-inflammatory glucocorticosteroids of the present invention also include the salts, hydrates, solvates and prod.ntg forms. The anti-inflammatory glucocorticosteroids of the present invention also include the isomers and metabolites of those described above.
100911 Salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, phosphonic acid, isonicotinate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate ( i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Other salts include, but are not limited to, salts with inorganic bases including alkali metal salts such as sodium salts, and potassium salts;
alkaline earth metal salts such as calcium. salts, and magnesium salts;
aluminum salts; and ammonium salts. Other salts with organic bases include salts with diethylamine, diethanolamine, meglumine, and ALIV-dibenzylethylenediamine.
100921 The neutral forms of the anti-inflammatory glucocorticosteroids can be regenerated by contacting the salt with a base or acid and isolating the parent anti-inflammatory glueocorticosteroid in the conventional manner. The parent form. of the anti-inflammatory glucocorticosteroid differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
[00931 Certain anti-inflammatory glucocorticosteroids of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain anti-inflammatory glucocorticosteroids of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[00941 Certain anti-inflammatory glucocorticosteroids of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present invention. The anti-inflammatory glucocorticosteroids of the present invention do not include those which are known in art to be too unstable to synthesize and/or isolate. The present invention is meant to include anti-inflammatory glucocorticosteroids in racemic and optically pure forms.
Optically active (R)-and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
[00951 The present invention also provides anti-inflammatory glucocorticosteroids which are in a prodrug form. Prodrugs of the anti-inflammatory glucocorticosteroids described herein are those anti-inflammatory glucocorticosteroids that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention.
Additionally, prodrugs can be converted to the anti-inflammatory glucocorticosteroids of the present invention by chemical or biochemical methods in an ay vivo environment. For example, prodrugs can be slowly converted to the anti-inflammatory glucocorticosteroids of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
V. Formulation 100961 The compositions of the present invention can be prepared in a wide variety of oral, parenteral and topical dosage forms. Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for ingestion by the patient. The compositions of the present invention can also be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Also, the compositions described herein can be administered by inhalation, for example, intranasally. Additionally, the compositions of the present invention can be administered transdermally. The compositions of this invention can also be administered by intraocular, intravaginal, and intrarectal routes including suppositories, insufflation, powders and aerosol formulations (for examples of steroid inhalants, see Rohatagi, J.
Clin. Pharmacol.

35:1187-1193, 1995; Tiwa, Ann. Allergy Asthma Immunol. 75:107-111, 1995).
Accordingly, the present invention also provides pharmaceutical compositions including a pharmaceutically acceptable carrier or excipient and a compound of the present invention.
[00971 For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid.
Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. Details on techniques for formulation and administration are well described in the scientific and patent literature, see, e.g., the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton PA ("Remington's").
100981 In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
The powders and tablets preferably contain from 5% or 10% to 70% of the compounds of the present invention.
100991 Suitable solid excipients include, but are not limited to, magnesium carbonate;
magnesium stearate; tale; pectin; dextrin; starch; tragacanth; a low melting wax; cocoa butter;
carbohydrates; sugars including, but not limited to, lactose, sucrose, mannitol, or sorbitol, starch from. corn, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose, or sodium carboxymethylcellulose; and gums including arabic and tragacantb; as well as proteins including, but not limited to, gelatin and collagen. If desired, disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrol.idone, agar, alginic acid, or a salt thereof, such as sodium alginate.
[01001 Dragee cores are provided with suitable coatings such as concentrated sugar solutions, which may also contain gum ara.bic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for product identification or to characterize the quantity of active compound (i.e., dosage). Pharmaceutical preparations of the invention can also be used orally using, for example, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating such as glycerol or sorbitol. Push-fit capsules can contain the compounds of the present invention mixed with a filler or binders such as lactose or starches, lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the compounds of the present invention may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers.
[01011 For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the compounds of the present invention arc dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
[01021 Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
[01031 Aqueous solutions suitable for oral use can be prepared by dissolving the compounds of the present invention in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium. carbox.ymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacarith and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatidc (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene ox.yeetariol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensation product of ethylene oxide with a partial ester derived from fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate). The aqueous suspension can also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin.
Formulations can be adjusted for ostnolarity.

01041 Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
101051 Oil suspensions can be formulated by suspending the compounds of the present invention in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin; or a mixture of these. The oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose. These formulations can be preserved by the addition of an antioxidant such as ascorbic acid. As an example of an injectable oil vehicle, see Minto, J. Pharmacol. Exp. Ther.
281:93-102, 1997. The pharmaceutical formulations of the invention can also be in the form of oil-in-water emulsions.
The oily phase can be a vegetable oil or a mineral oil, described above, or a mixture of these.
Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum.
tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan m.ono-oleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. The emulsion can also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs. Such formulations can also contain a demulcent, a preservative, or a coloring agent.
[01061 The compositions of the present invention can also be delivered as microspheres for slow release in the body. For example, microspheres can be formulated for administration via intradermal injection of drug-containing microspheres, which slowly release subcutaneously (see Rao, J. .Biomater S'ci. Polym. Ed. 7:623-645, 1995; as biodegradable and injectable gel formulations (see, e.g., Gao Phann. Res. 12:857-863, 1995); or, as microspheres for oral administration (see, e.g., Eyles, J. .Pharm. Pharmacol. 49:669-674, 1997).
Both transdertnal and intradermal routes afford constant delivery for weeks or months.
101071 In another embodiment, the compositions of the present invention can be formulated for parenteral administration, such as intravenous (IV) administration or administration into a body cavity or lumen of an organ. The formulations for administration will commonly comprise a solution of the compositions of the present invention dissolved in a pharmaceutically acceptable carrier. Among the acceptable vehicles and solvents that can be employed are water and Ringer's solution, an isotonic sodium chloride. In addition, sterile fixed oils can conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can likewise be used in the preparation of injectables. These solutions are sterile and generally free of undesirable matter. These formulations may be sterilized by conventional, well known sterilization techniques. The formulations may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH
adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium.
chloride, potassium.
chloride, calcium chloride, sodium lactate and the like. The concentration of the compositions of the present invention in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of administration selected and the patient's needs. For IV administration, the formulation can be a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally-acceptable diluent or solvent, such as a solution of 1,3-butanediol.
101081 In another embodiment, the formulations of the compositions of the present invention can be delivered by the use of I.iposomes which fuse with the cellular membrane or are endocytosed, i.e., by employing ligands attached to the liposome, or attached directly to the oligonueleotide, that bind to surface membrane protein receptors of the cell resulting in endocytosis. By using liposomes, particularly where the liposome surface carries ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery of the compositions of the present invention into the target cells in vivo. (See, e.g., Al-Muhammed, J. Microencapsul. 13;293-306, 1996; Chonn, Curr. Opin.
Biotechnol. 6:698-708, 1995; Ostro, Hosp. Pharm. 46:1576-1587, 1989).

01091 Lipid-based drug delivery systems include lipid solutions, lipid emulsions, lipid dispersions, self-emulsifying drug delivery systems (SEDDS) and self-microemulsifying drug delivery systems (SMEDDS). In particular, SEDDS and SMEDDS are isotropic mixtures of lipids, surfactants and co-surfactants that can disperse spontaneously in aqueous media and form fine emulsions (SEDDS) or microemulsions (SMEDDS). Lipids useful in the formulations of the present invention include any natural or synthetic lipids including, but not limited to, sesame seed oil, olive oil, castor oil, peanut oil, fatty acid esters, glycerol esters, Labrafil(R), Labrasol , Cremophor , Solutol , Tween , Capryoll), Capmul , Captex , and PeceoW.
V1. Administration 101101 The compounds and compositions of the present invention can be delivered by any suitable means, including oral, parenteral and topical methods. Transdermal administration methods, by a topical route, can be formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.
[01111 The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the compounds and compositions of the present invention. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
101121 The compounds and compositions of the present invention can be co-administered with other agents. Co-administration includes administering the compound or composition of the present invention within 0.5, 1, 2, 4, 6, 8, 10, 12, 16,20, or 24 hours of the other agent. Co-administration also includes administering simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order.
Moreover, the compounds and compositions of the present invention can each be administered once a day, or two, three, or more times per day so as to provide the preferred dosage level per day.

01131 In some embodiments, co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including the compounds and compositions of the present invention and any other agent. Alternatively, the various components can be formulated separately.
[01141 The compounds and compositions of the present invention, and any other agents, can be present in any suitable amount, and can depend on various factors including, but not limited to, weight and age of the subject, state of the disease, etc. Suitable dosage ranges include from about 0.1 mg to about 10,000 mg, or about 1 mg to about 1000 mg, or about 10 mg to about 750 mg, or about 25 mg to about 500 mg, or about 50 mg to about 250 mg. Suitable dosages also include about 1 mg, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000 mg.
101151 The composition can also contain other compatible therapeutic agents.
The compounds described herein can be used in combination with one another, with other active agents known to be useful in modulating a glucocorticoid receptor, or with adjunctive agents that may not be effective alone, but may contribute to the efficacy of the active agent.
VD. Methods of Modulating a Cancocorticoid Receptor and Treating a Disorder 101161 In some embodiments, the present invention provides a method of modulating a glucocorticoid receptor, the method including contacting a glucocorticoid receptor with a compound of the present invention, thereby modulating the glucocorticoid receptor.
101171 In some embodiments, the present invention provides a method of treating a disorder through modulating a glucocorticoid receptor, the method including administering to a subject in need of such treatment, a therapeutically effective amount of a compound of the present invention, thereby treating the disorder.
101181 In some other embodiments, the present invention provides a method of treating a disorder through antagonizing a glucocorticoid receptor, the method including administering to a subject in need of such treatment, an effective amount of the compound of the present invention, thereby treating the disorder.

01191 In another embodiment, the present invention provides methods of modulating glucocorticoid receptor activity using the techniques described herein. In an exemplary embodiment, the method includes contacting a OR with an effective amount of a compound of the present invention, such as the compound of the present invention, and detecting a change in OR activity.
101201 In an exemplary embodiment, the OR modulator is an antagonist of OR
activity (also referred to herein as "a glucocorticoid receptor antagonist"). A
glucocorticoid receptor antagonist, as used herein, refers to any composition or compound which partially or completely inhibits (antagonizes) the binding of a glucocorticoid receptor (OR) agonist (e.g. cortisol and synthetic or natural cortisol analog) to a OR thereby inhibiting any biological response associated with the binding of a OR to the agonist.
101211 In a related embodiment, the OR modulator is a specific glucocorticoid receptor antagonist. As used herein, a specific glucocorticoid receptor antagonist refers to a composition or compound which inhibits any biological response associated with the binding of a OR to an agonist by preferentially binding to the OR rather than another nuclear receptor (NR). In some embodiments, the specific glucocorticoid receptor antagonist binds preferentially to OR rather than the minemlocorticoid receptor (MR) or progesterone receptor (PR). In an exemplary embodiment, the specific glucocorticoid receptor antagonist binds preferentially to GR. rather than the mineralocorticoid receptor (MR). In another exemplary embodiment, the specific glucocorticoid receptor antagonist binds preferentially to OR rather than the progesterone receptor (PR).
[01221 In a related embodiment, the specific glucocorticoid receptor antagonist binds to the OR with an association constant (K4 that is at least 10-fold less than the Kd for other nuclear receptor. In another embodiment, the specific glucocorticoid receptor antagonist binds to the OR
with an association constant (IQ that is at least 100-fold less than the Kd for the other nuclear receptor. In another embodiment, the specific glucocorticoid receptor antagonist binds to the OR
with an association constant (K) that is at least 1000-fold less than the Kd for the other nuclear receptor.
101231 Examples of disorders or conditions suitable for use with present invention include, but are not limited to, obesity, diabetes, cardiovascular disease, hypertension, Syndrome X, depression, anxiety, glaucoma, human immunodeficiency virus (H1V) or acquired immunodeficiency syndrome (AIDS), neurodegeneration, Alzheimer's disease, Parkinson's disease, cognition enhancement, Cushing's Syndrome, Addison's Disease, osteoporosis, frailty, muscle frailty, inflammatory diseases, osteoarthritis, rheumatoid arthritis, asthma and rhinitis, adrenal function-related ailments, viral infection, immunodeficiency, immunomodulation, autoimmune diseases, allergies, wound healing, compulsive behavior, multi-drug resistance, addiction, psychosis, anorexia, cachexia, post-traumatic stress syndrome, post-surgical bone fracture, medical catabolism, major psychotic depression, mild cognitive impairment, psychosis, dementia, hyperglycemia, stress disorders, antipsychotic induced weight gain, delirium, cognitive impairment in depressed patients, cognitive deterioration in individuals with Down's syndrome, psychosis associated with interferon-alpha therapy, chronic pain, pain associated with gastroesophageal reflux disease, postpartum psychosis, postpartum depression, neurological disorders in premature infants, and migraine headaches. In some embodiments, the disorder or condition can be major psychotic depression, stress disorders or antipsychotic induced weight gain. In other embodiments, the disorder or condition can be Cushing's Syndrome.
A. Binding Assays [01241 OR modulators of this invention can be tested for binding activity in a variety of assays.
For example, by screening for the ability to compete with a OR ligand, such as dexamethasone, for binding to the glucocorticoid receptor. Those of skill in the art will recognize that there are a number of ways to perform such competitive binding assays. In som.e embodiments. OR is pre-incubated with a labeled GR ligand and then contacted with a test compound.
This type of competitive binding assay may also be referred to herein as a binding displacement assay.
Alteration (e.g., a decrease) of the quantity of ligand bound to OR indicates that the molecule is a potential OR modulator. Alternatively, the binding of a test compound to OR
can be measured directly with a labeled test compound. This latter type of assay is called a direct binding assay.
[01251 Both direct binding assays and competitive binding assays can be used in a variety of different formats. The formats may be similar to those used in immunoassays and receptor binding assays. For a description of different formats for binding assays, including competitive binding assays and direct binding assays, see Basic and Clinical immunology 7th Edition (D.
Stites and A. Terr ed.) 1991; Enzyme Immunoassay, E.T. Maggio, ed., CRC Press, Boca Raton, Florida (1980); and "Practice and Theory of Enzyme Immunoassays," P. Tijssen, Laboratory Techniques in Biochemistry and Molecular Biology, Elsevier Science Publishers B.V.
Amstcrdam (1985).
[0126] In solid phase competitive binding assays, for example, the sample compound can compete with a labeled analyte for specific binding sites on a binding agent bound to a solid surface. In this type of format, the labeled analyte can be a GR ligand and the binding agent can be GR bound to a solid phase. Alternatively, the labeled analyte can be labeled GR and the binding agent can be a solid phase GR ligand. The concentration of labeled analyte bound to the capture agent is inversely proportional to the ability of a test compound to compete in the binding assay.
[0127] Alternatively, the competitive binding assay may be conducted in liquid phase, and any of a variety of techniques known in the art may be used to separate the bound labeled protein from the unbound labeled protein. For example, several procedures have been developed for distinguishing between bound ligand and excess bound ligand or between bound test compound and the excess unbound test compound. These include identification of the bound complex by sedimentation in sucrose gradients, gel electrophoresis, or gel isoelectric focusing; precipitation of the receptor-ligand complex with protamine sulfate or adsorption on hydroxylapatite; and the removal of unbound compounds or ligands by adsorption on dextran-coated charcoal (DCC) or binding to immobilized antibody. Following separation, the amount of bound ligand or test compound is determined.
[0128] Alternatively, a homogenous binding assay may be performed in which a separation step is not needed. For example, a label on the GR may be altered by the binding of the GR to its ligand or test compound. This alteration in the labeled GR results in a decrease or increase in the signal emitted by label, so that measurement of the label at the end of the binding assay allows for detection or quantitation of the GR in the bound state. A wide variety of labels may be used. The component may be labeled by any one of several methods. Useful radioactive , ,,, 32 labels include those incorporating 3H, 1251 35s, 14u or -P. Useful non-radioactive labels include those incorporating fluorophores, chemiluminescent agents, phosphorescent agents, electrochemiluminescent agents, and the like. Fluorescent agents are especially useful in analytical techniques that are used to detect shifts in protein structure such as fluorescence CA 287'2260 2019-05-10 anisotropy and/or fluorescence polarization. The choice of label depends on sensitivity required, ease of conjugation with the compound, stability requirements, and available instrumentation.
For a review of various labeling or signal producing systems which may be used, see U.S. Patent No. 4,391,904. The label may be coupled directly or indirectly to the desired component of the assay according to methods well known in the art.
[0129] High-throughput screening methods may be used to assay a large number of potential modulator compounds. Such "compound libraries" are then screened in one or more assays, as described herein, to identify those library members (particular chemical species or subclasses) that display a desired characteristic activity. Preparation and screening of chemical libraries is well known to those of skill in the art. Devices for the preparation of chemical libraries are commercially available (see, e.g., 357 MPS, 390 MPS, Advanced Chem Tech, Louisville KY, Symphony, Rainin, Woburn, MA, 433A Applied Biosystems, Foster City, CA, 9050 Plus, Millipore, Bedford, MA).
B. Cell-Based Assays [01301 Cell-based assays involve whole cells or cell fractions containing GR
to assay for binding or modulation of activity of GR by a compound of the present invention. Exemplary cell types that can be used according to the methods of the invention include, e.g., any mammalian cells including leukocytes such as neutrophils, monoeytes, macrophages, eosinophils, basophils, mast cells, and lymphocytes, such as T cells and B cells, leukemias, Burkitt's lymphomas, tumor cells (including mouse mammary tumor virus cells), endothelial cells, fibroblasts, cardiac cells, muscle cells, breast tumor cells, ovarian cancer carcinomas, cervical carcinomas, glioblastomas, liver cells, kidney cells, and neuronal cells, as well as fungal cells, including yeast. Cells can be primary cells or tumor cells or other types of immortal cell lines. Of course, GR can be expressed in cells that do not express an endogenous version of GR.
[01311 In some cases, fragments of GR, as well as protein fusions, can be used for screening.
When molecules that compete for binding with GR ligands are desired, the OR
fragments used are fragments capable of binding the ligands (e.g., dexamethasone).
Alternatively, any fragment of GR can be used as a target to identify molecules that bind GR. OR fragments can include any fragment of, e.g., at least 20, 30, 40, 50 amino acids up to a protein containing all but one amino acid of GR.
[01321 In some embodiments, signaling triggered by GR activation is used to identify GR
modulators. Signaling activity of OR can be determined in many ways. For example, downstream molecular events can be monitored to determine signaling activity.
Downstream events include those activities or manifestations that occur as a result of stimulation of a OR
receptor. Exemplary downstream events useful in the functional evaluation of transcriptional activation and antagonism in unaltered cells include upregulation of a number of glucocorticoid response element (GRE)-dependent genes (PEPCK, tyrosine amino transferase, aromatase). In addition, specific cell types susceptible to GR activation may be used, such as osteocalcin expression in osteoblasts which is downregulated by glucocorticoids; primary hepatecres which exhibit glucocorticoid mediated upregulation of PEPCK and glucose-6-phospahte (G-6-Pase)).
GRE-mediated gene expression has also been demonstrated in transfected cell lines using well-known GRE-regulated sequences (e.g. the mouse mammary tumor virus promoter (MMTV) transfected upstream of a reporter gene construct). Examples of useful reporter gene constructs include luciferase (luc), alkaline phosphatase (ALP) and chloramphenicol acetyl transferase (CAT). The functional evaluation of transcriptional repression can be carried out in cell lines such as monocytes or human skin fibroblasts. Useful functional assays include those that measure IL-lbeta stimulated IL-6 expression; the downregulation of collagenase, cyclooxygenase-2 and various chemokines (MCP-1, RANTES); LPS stimulated cytokine release, e.g., TNFa.; or expression of genes regulated by NFkB or AP-1 transcription factors in transfected cell-lines.
101331 Typically, compounds that are tested in whole-cell assays are also tested in a cytotoxicity assay. Cytotoxicity assays are used to determine the extent to which a perceived modulating effect is due to non-OR binding cellular effects. In an exemplary embodiment, the cytotoxicity assay includes contacting a constitutively active cell with the test compound. Any decrease in cellular activity indicates a cytotoxic effect.

C. Specificity [0134] The compounds of the present invention may be subject to a specificity assay (also referred to herein as a selectivity assay). Typically, specificity assays include testing a compound that binds GR in vitro or in a cell-based assay for the degree of binding to non-GR
proteins. Selectivity assays may be performed in vitro or in cell based systems, as described above. Binding may be tested against any appropriate non-GR protein, including antibodies, receptors, enzymes, and the like. In an exemplary embodiment, the non-GR
binding protein is a cell-surface receptor or nuclear receptor. In another exemplary embodiment, the non-GR
protein is a steroid receptor, such as estrogen receptor, progesterone receptor, androgen receptor, or mineralocorticoid receptor.
[0135] The terms and expressions which have been employed herein are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding equivalents of the features shown and described, or portions thereof, it being recognized that various modifications are possible within the scope of the invention claimed. Moreover, any one or more features of any embodiment of the invention may be combined with any one or more other features of any other embodiment of the invention, without departing from the scope of the invention. For example, the features of the GR
modulator compounds are equally applicable to the methods of treating disease states and/or the pharmaceutical compositions described herein.
VIII. Methods of Treating and Reducing Steroid Side Effects [0136] The compounds and compositions of the present invention are useful in a variety of methods such as treating a disorder or condition or reducing the side effects of glucocorticosteroid treatment.
[0137] In some embodiments, the present invention provides a method of inhibiting glucocorticoid receptor (GR) induced transactivation without substantially inhibiting GR-induced transrepression, wherein the method includes contacting a GR with a composition including an anti-inflammatory glucocorticosteroid able to induce both GR
transactivation and OR transrepression, and a GR modulator of the present invention, in an amount sufficient to inhibit GR induced transactivation without substantially inhibiting OR-induced transrepression, thereby inhibiting OR induced transactivation without substantially inhibiting OR-induced transrepression. In some embodiments, the method of inhibiting glucocorticoid receptor (OR) induced transactivation without substantially inhibiting OR-induced transrepression, includes contacting the OR with a composition including the compound (R)-(1-(4-fluoropheny1)-6-04-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro- I H-pyrazo I o[3,4-g] soquinoli n-4a-yl)(thiazol-2-y1)methanone.
101381 For those OR modulators of the present invention that can inhibit transactivation, the compounds can inhibit transactivation when GR induced transactivation of gene expression is reduced by at least about 50%, relative to the level of gene expression observed in the absence of the OR modulator. For example, OR induced transactivation can be inhibited by at least about 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 96. 97, 98 or 99%. In some embodiments, glucocorticoid receptor induced transactivation is inhibited by at least about 50%. In other embodiments, glucocorticoid receptor induced transactivation is inhibited by at least about 65%. In som.e other embodiments, glucocorticoid receptor induced transactivation is inhibited by at least about 75%.
In still other embodiments, glucocorticoid receptor induced transactivation is inhibited by at least about 85%. In yet other embodiments, glucocorticoid receptor induced transactivation is inhibited by at least about 95%.
[0139] For those OR modulators of the present invention that can inhibit transactivation, some of the OR modulators may be able do so while not substantially inhibiting GR-induccd transrepression activity. For example, GR-induced transrepression is considered not substantially inhibited when, in the presence of the composition of the present invention, the GR-induced transrepression activity is inhibited by less than about 75%, relative to the level of GR-induced transrepression activity in the absence of the OR modulator of the present invention.
OR-induced transrepression is also considered not substantially inhibited when the OR-induced transrepression activity is inhibited by less than about 70, 60, 50, 40, 35, 30, 25, 20, 15, 10, 5, 4, 3, 2 or 1%, relative to the level of OR-induced transrepression activity in the absence of the GR
modulator of the present invention. In some embodiments, OR-induced transrepression activity is inhibited by less than about 50%. In other embodiments, GR-induced transrepression activity is inhibited by less than about 25%. In some other embodiments, GR-induced transrepression activity is inhibited by less than about 10%.
[0140] In other embodiments, the ratio of percent inhibition of GR induced transactivation inhibition to percent inhibition of OR-induced transrepression inhibition can be from about 1000 to 1. For example, the ratio of percent inhibition of OR induced transactivation inhibition to percent inhibition of OR-induced transrepression inhibition can be about 1000, 500, 100, 90, 80, 70, 60, 50, 40, 30, 25, 20, 15, 10, 5, 4, 3, 2, or 1.
[0141] In some other embodiments, the OR induced transactivation is caused by the anti-inflammatory glucocorticosteroid described above.
101421 In some embodiments, the present invention provides a method of treating a disorder or condition, including administering to a subject in need thereof, a therapeutically effective amount of a composition including an anti-inflammatory glucocorticosteroid and a OR
modulator of the present invention. In some other embodiments, the anti-inflammatory glucocorticosteroid and GR modulator of the present invention modulate the activity of a GR. The diseases and conditions include, among other, inflammatory conditions and autoimmune diseases. In some embodiments, the disorder or condition can be glaucoma, inflammatory diseases, rheumatoid arthritis, asthma and rhinitis, allergies and autoimmune diseases.
Representative autoimmune disease include, but are not limited to, obstructive airways disease, including conditions such as COPD, asthma (e.g. intrinsic asthma, extrinsic asthma, dust asthma, infantile asthma), bronchitis, including bronchial asthma, systemic lupus erythematosus (SLE), multiple sclerosis, type I
diabetes mellitus and complications associated therewith, atopic eczema (atopic dermatitis), contact dermatitis and further eczem.atous dermatitis, inflammatory bowel disease (e.g. Crohn's disease and ulcerative colitis), atherosclerosis and amyoixophic lateral sclerosis. Other autoim.mune diseases include tissue and organ transplants, and allergies.
[0143] In some embodiments, the present invention provides a method of reducing the side effects of glucocorticosteroid treatment, including administering to a subject in need thereof, a therapeutically effective amount of a composition including an anti-inflammatory glucocorticosteroid and a OR modulator having the structure of the present invention. In some embodiments, the side effects of glucocorticosteroid treatment can be weight gain, glaucoma, fluid retention, increased blood pressure, mood swings, cataracts, high blood sugar, diabetes, infection, loss of calcium from bones, osteoporosis, or menstrual irregularities. Additional side effects include muscle wasting, fat redistribution, growth retardation and cushingoid appearance.
[0144] Other conditions that can be treated using the compounds of the present invention include alcohol dependence, symptoms of alcohol withdrawal, and cognitive deficits associated .. with excess alcohol consumption. The compounds of the present inventin can also be used to treat cancer, such as cancer of the bone, breast, prostate, ovary, skin, brain, bladder, cervix, liver, Lung, etc. Other cancers that can be treated using the compounds of the present invention include Leukemia, lymphoma, neuroblastoma, among others. When administered for the treatment of cancer, the compounds of the present invention can be administered separately or in combination with an antineoplastic agent such as taxanes, taxol, docetaxel, paclitaxel, actinomycin, anthracyclines, doxorubicin, di un orubicin, valrubicin, bleomycin, cisplatin, among others.
Assays to Identify GR Modulators [01451 OR modulators of this invention can be tested for inhibition of OR
induced transactivation while not substantially inhibiting GR-induced transrepression in a variety of assays. OR modulators of the present invention that inhibit OR induced transactivation can be identified by measuring the amount of tyrosine amino transferase expressed in the presence of the OR induced transactivation in a cell model (human liver hepatocytes). OR
modulators usettil in the present invention can be those that inhibit OR. induced transactivation by at least about 50%.
[0146] Moreover, for the OR. modulators of the present invention that induce transactivation, some may be able to do so while not inhibiting the OR-induced transrepression activity by more than about 50%. Specifically, the compositions of the present invention that can induce transactivation while not substantially inhibiting the OR-induced transrepression activity of dexamethasone with regard to LPS activated TNRY. release (N1FKB responsive gene), can be identified using a cell-based model (human peripheral blood mononuclear cells), dexamethasone can be administered to the cells and the release of TNFa can be measured.
After addition of the GR modulator of the present invention, the release of TNFot can be again measured and compared to the amount released in the absence of the GR. modulator. A OR
modulator of the present invention that does not substantially block the effect of dexamethasone, does not substantially inhibit GR-induced transrepression.
IX. Examples 101471 Structures are named according to standard RJPAC nomenclature using the CambridgeSoft ChemDraw naming package.
101481 1H NMR spectra were recorded at ambient temperature using a Varian Unity Inova spectrometer (400 MHz) with a 5 mm inverse detection triple resonance probe for detection of HI. CI3 and P31 or a Brttker Avance DRX spectrometer (400 MHz) with a 5 mm inverse detection triple resonance TXI probe, or a Bruker Avance 111 spectrometer (400 MHz).
101491 Mass spectrometry (LCMS) experiments to determine retention times and associated mass ions were performed using the following methods:
101501 Method A: experiments were performed using a Waters Platform LC
quadrupole mass spectrometer with positive and negative ion electrospray and ELS / Diode array detection using a Phenomenex Luna 3 micron C18 (2) 30 x 4.6 mm. column and a 2 mL / minute flow rate. The solvent system was 95% water containing 0.1% formic acid (solvent A) and 5%
ace tonitrile containing 0.1% formic acid (solvent B) for the first 50 seconds followed by a gradient up to 5%
solvent A and 95% solvent B over the next 4 minutes. The final solvent system was held constant for a further 1 minute.
[01511 Method B: experiments were performed using a VG Platform 11 quadrupole mass spectrometer with a positive and negative ion electrospray and ELS / Diode array detection using a Phenomenex Luna 3 micron C18 (2) 30 x 4.6 mm column and a 2 mL / minute flow rate. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5%
acetonitrile containing 0.1% formic acid (solvent B) for the first 30 seconds followed by a gradient up to 5% solvent A and 95% solvent B over the next 4 minutes. The final solvent system was held constant for a further 2 minutes.
101521 Method C: experiments were performed using a Waters ZMD quadrupole mass spectrometer with positive and negative ion electrospray and ELS / Diode array detection using a Phenomenex Luna 3 micron C18 (2) 30 x 4.6 mm column and a 2 mL / minute flow rate. The solvent system was 95% water containing 0.1% formic acid (solvent A) and 5%
acetonitrile containing 0.1% formic acid (solvent B) for the first 50 seconds followed by a gradient up to 5% solvent A and 95% solvent B over the next 4 minutes. The final solvent system was held constant for a further 1 minute.
[0153] Method D: experiments were performed using a Waters Micromass ZQ2000 quadrupole mass spectrometer linked to a Waters Acquity UPLC system with a PDA
UV
detector using an Acquity UPLC BEI I CI8 1.7micron 100x2.1mm, maintained at 40 C. The spectrometer has an electrospray source operating in positive and negative ion mode. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5%
acetonitrile containing 0.1% formic acid (solvent B) for 0.4 minutes followed by a gradient up to 5%
solvent A and 95% solvent B over the next 6.4 minutes.
[0154] Method E: experiments were performed using a Waters Micromass ZQ2000 quadrupole mass spectrometer linked to a Hewlett Packard HP1100 LC system with a DAD
UV detector using a Higgins Clipeus 5 micron C18 100x3.0mm, maintained at 40 C. The spectrometer has an electrospray source operating in positive and negative ion mode. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5%
acetonitrile containing 0.1% formic acid (solvent B) for 1.0 minutes followed by a gradient up to 5%
solvent A and 95% solvent B over the next 15 minutes. The final solvent system was held constant for a further 5 minutes.
[0155] Method F: experiments were performed using an AgilentTM Infinity 1260 quadrupole mass spectrometer with positive and negative ion electrospray and ELS / UV @
254nm detection using an AgilentTM Zorbax Extend C18, Rapid Resolution HT 1.8 micron C18 30 x 4.6 mm column and a 2.5 mI, /minute flow rate. The initial solvent system was 95%
water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) ramping up to 5% solvent A and 95% solvent B over the next 3.0 minutes, the flow rate was then increased to 4.5 mL / minute and held for 0.5 minutes at 95% B.
Over 0.1 minute the gradient was returned to 95% A and 5% B and 3.5 mL / minute and was held at these conditions for 0.3 minutes; the final 0.1 minute resulted in the return to the initial starting conditions, 95% A 5% B at 2.5 mL /minute.

CA 284'2260 2019-05-10 Intermediate 1. (R)-1-(4-fluoronhenv1)-6-((4-(ttifluoromethvflphtnst)sulfonv1)-4,4a,5,6,7,8-hexahvdro-IH-pyrazolo13.4-disoaninoline-4a-earbaldehvde and Intermediate 2. (11)-(1-(4-11uorophenv1)-6-((44tr1fluoromethvI)pheathsnifoncl)-4,4aõ5.6.7,8-hexahvdro-lH-pvraz01o13.4-2.1isocguirio1i11-4a-V1)Mutila#10i H 00 0 H0,, 00 \+.
N...S
Ni I N
µ14 F F
Intermediate]. Intermediate 2 101561 A solution of (R)-methyl 1-(4-fluoropheny1)-6-44-(trifluoromethyl)phenyl)sulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-glisoquinoline-4a-carboxylate (2.12 g, 3.96 mmol) was dissolved in dry dichloromethane and cooled to -78 C under nitrogen. A
solution of diisobutylaluminiurn hydride (1.0 M in dichloromethane, 16 rnmol, 16 mL) was added dropwise maintaining the reaction temperature at <-70 C and the reaction mixture was stirred at -78 C for 1 hour. The reaction mixture was treated with water (6 mL), stirred at -78 C
for 5 minutes then warmed to >0 C over 15 minutes. Solid sodium bicarbonate (5.5 g) was added and the mixture stirred vigorously for 5 minutes. Excess sodium sulfate was added (-20 g) and the resultant mixture was stirred vigorously for a further 15 minutes. The solid materials were removed by filtration and rinsed with a little dichloromethane. The filtrate was concentrated under reduced pressure and the residue purified by column chromatography on silica gel eluting with a mixture of ethyl acetate and cyclohexane (3;7 by volume) followed by ethyl acetate to afford (R)-1-(4-fluoropheny1)-6-((4-(trifluoromethyl)phenyl)sulfony1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-g]isoquinoline-4a-carbaldehyde as a white foam (0.62 g). 1H NMR (400 MHz, CDC13): 9.48 (s, 1 H); 7.93 (d, J = 8.2 Hz, 2 H); 7.84 (d, J = 8.3 Hz, 2 H); 7.39-7.40 (m, 3 H); 7.17 (t, J= 8.5 Hz.
2 H); 6.52 (d. J = 2.5 Hz, 1 H); 4.32 (d, J = 12.3 Hz, 1 H); 3.90 (br s. 1 H);
3.14 (d, J= 16.4 Hz, 1 H); 2.65-2.80 (m, 1H); 2.51-2.52 (m, 4 H) and (R)-(1-(4-fluoropheny1)-644-(trifluoromethyl)pheriy1) sulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)methanol as a white solid (1.0 g). 1H NMR (400 MHz, CDCI3): 8 7.94 (d, J=
8.2 Hz, 2 H);
7.83 (d, J = 8.3 Hz, 2 H); 7.40-7.41 (m, 3 11); 7.14-7.15 (m, 2 H); 6.31 (d, J
= 2.4 Hz, 1 H); 4.11-4.12 (m, 1 H); 4.02 (dd, j = 11.4,5.9 Hz, 1 H); 3.78 (dd,J = 11.5, 5.6 Hz, 1 H); 3.34 (dd, J =
11.4, 8.1 Hz, 1 H); 3.13 (d, J = 15.8 Hz, 1 H); 2.74-2.76 (m, 1 H); 2.59-2.60 (m, 1 H); 2.41 (d, J
= 15.5 Hz, 1 H); 2.24-2.25 (m, 2 H); 2.04 (s, 1 H).
Intermediate 1. (it )- I -(4- fluorophenv1)-6-04-(trifluoromethOphenvOsul fonvI)-4,4a,5.6.7,8-.. hexahvdro-1H-pyrazola3,4-glisom inoline-4a-carbaldehvde 101571 A solution of oxalyl chloride (7.35 g, 58.8 mmol) in dry dichloromethane (160 mL) was cooled to -60 C under nitrogen and treated dropwise with dry dimethyl sulfoxide (9.55 g, 122.5 mmol) such that the temperature did not rise above -50 C. *the mixture was stirred at -55 C for minutes. A solution of (R)-(1-(4-fluoropheny1)-644-(trifluoromethyl)phenyl)sulfony1)-10 4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)methanoi (12.40 g, 24.5 mmol) in dry dichlorornethane (140 mL) was added such that the temperature did not rise above -50 C.
The mixture was stirred for 2 hours allowing the temperature to rise to -15 C.
Triethylamine (12.64g, 125 mmol) was added dropwise such that the temperature did not rise above -5 C and the resultant mixture was stirred until the temperature reached 0 C. Water (100 mi.) was added, 15 the phases were separated, the aqueous phase was extracted with further dichloromethane (x2) and the combined organic phases were dried over sodium sulfate. The solids were removed by filtration, the filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with a mixture of ethyl acetate and dichloromethane (1:1 by volume) followed by ethyl acetate to afford (R)-1-(4-fluorophenyI)-6-((4-(trifluoromethyl)phenypsulfony1)-4,4a,5,6,7,8-hexahydro-IFI-pyrazolo[3,4-disoquinoline-4a-carbaldehyde as a white foam (11.8 g). Iii NMR (400 MHz, CDCI3): 6 9.48 (s, 1 H); 7.93 (d, J = 8.2 Hz, 2 H); 7.84 (d, J = 8.3 Hz, 2 H); 7.39-7.40 (m, 3 H); 7.15-7.16 (m, 2 H); 6.52 (d, J
2.4 Hz, 1 H); 4.32 (dd, J = 12.2, 2.1 Hz, 1 II); 3.90 (dd, J = 11.0, 5.6 Hz, 1 H); 3.14 (d, J = 16.4 Hz, 1 H); 2.71-2.73 (in, 1 H); 2.60 (d, 3 16.4 Hz, 1 H); 2.49-2.51 (m, 3 H).
intermediate 3. (R)-(1.-(4-fleoroahetiv1)-6-((4.-ftrifluoroinethamhenvi)sulfon v1)-4.4a4.6,7.8-hexa vdro-111-ovrazolof3A-glisoci uitiolin-4a-v1)(1)vridin-2-vi)-(RIS )- metha noi LJLoH 0 0 NI N = = = =
F
F
I1)1581 2-Bromopyridine (6.50 g, 40 mmol) was added to isopropyl magnesium chloride (2.0 M solution in tetrahydrofuran, 20 mL, 40 mmol) at room temperature. The mixture was stirred for 10 minutes then warmed to 30 C and stirred for 105 minutes. The mixture was cooled to -10 C and a solution of (R)-1-(4-fluoropheny1)-6-04-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5õ6,7,8-hexahydro-lH-pyrazolo[3,4-g]isoquinolinc-4a-carbaldchydc (5.5g, 10 mmol) in tetrahydrofiiran (9 niL) was added dropwise. The reaction mixture was stirred for 15 minutes at -10 C followed by stirring at room temperature for 1 hour. The reaction mixture was cooled and treated with water (20 nil) followed by aqueous hydrochloric acid (1.0 M, 40 The mixture was stirred for 10 minutes then extracted with dichloromethane (x2) and the combined organic phases dried over sodium. sulfate. The solids were removed by filtration, the filtrate was concentrated under reduced pressure and the residue purified by column chromatography on.
silica gel (gradient: 20-80% ethyl acetate in cyclohexane) to afford the diastereoisomerie (2:1) mixture (R)-(1-(4-fluoropheny1)-6-44-(trifluorom.ethypphenyl)sul fony1)-4,4a,5,6,7,8-hex.ahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-y1)-(R/S)-methanol as an off-white foam (3.25 g). 1H NMR (400 MHz, CDCI3): 6 8.29 (d, J = 4.8 Hz, 1 H); 8.00 (d, J = 8.2 Hz, 2 H); 7.84-7.86 (m, 3 H); 7.44-7.46 (m, 1 H); 7.29-7.30 (m, 1.5 H); 7.09-7.10 (m., 3.5 H); 6.95-6.97 (m, 2.5 H); 6.41 (s, 0.5 H); 6.18 (s, 1 H); 5.11 (s, 0.5 H); 5.04 (s, 1 H); 4.87 (s, I
H); 4.50 (d, J 11.8 Hz, 1 H); 4.10(d, J = 13.3 Hz, 2.5 H); 3.80 (d, J = 12.1 Hz, 0.5 H); 3.69 (s, 0.5 H); 3.24 (d, J =
16.6 Hz, 1 H); 3.09-3.13 (m, 1..5 H); 2.54-2.58 (m, 2.5 H); 2.25-2.27 (m, 1 H);2.11 (d, J= 16.6 Hz, 1 H); 1.43 (s, 0.5 Fl).
101591 The following intermediate 4 was similarly prepared from the appropriate starting materials:
Intermediate 4. (R)-(1-(4-fluoropheny1)-6-((4-(trilluoromethypphenybsulfonvi)-4.4a..5.6,7.8-hexahvdro-1H-pyrazolo[3,4-glisoquinolin-4a-y1)(pyridin-3-v1)-(R/S)-methanol , Ni I
F
101601 LCMS (Method C, ES1): RT 2.84 min, m+H = 585.1; 1H NMR (400 MHz, CDC13): 5 8.33 (d, = 2.2 Hz, 1 H); 8.18 (dd, J = 4.8, 1.7 Hz, 1 H); 7.97 (d, J = 8.2 Hz, 2 H); 7.85 (d, J =
8.2 Hz, 2 H); 7.69 (d, i = 8.0 Hz, 1 H); 7.04-7.05 (m, 4 H); 6.92 (dd, J =
7.9,4.8 Hz, 1 H); 6.10 (d, J = 2.3 Hz,! H); 5.18 (s, 1 H); 4.34 (dd, J = 12.3, 2.3 Hz, 1 H); 4.15 (d, J= 11.2 Hz, 1 H);
3.42(d, J = 16.8 Hz, 1 H); 3.25 (s, 1 H); 2.66 (t, J = 12.0 Hz, 1 H); 2.52 (d, J= 15.4 Hz, 1 H);
2.34 (d, J = 12.3 Hz, 1 H); 2.17 (d, J = 16.8 Hz, 1 H).
Intermediate 5. (R)-(1-(4-fluorouhenv1)-6-((4-(trifluoromethvI)DhenvI)sulfonv11-4,4a,5.6,7,8-hi?NatiVdro-111-m razolol 3.4-211so9uinolin-4a-v1)(1-methyl-1H-imidazol-2-y1)-(1RIS)-methanol =Nr- H
N/ I = I

F
[01611 2-Bromo-1-methy1-1H-imidazole (47 tiL, 0.48 mmol) was dissolved in diethyl ether (2 mL) and cooled to -75 C under argon. Butyl lithium (2.5 M in hexanes; 192 !IL, 0.48 mmol) was added dropwise and the mixture stirred at -75 C for 1 hour. A solution of (R)-1-(4-fluoropheny1)-6-04-(triflu.oromethyl)phenyt)sulfonyl)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-disoquinoline-4a-carbaldebyde (252 mg, 0.5 mmol) in diethyl ether (2 mL) was added dropwise.
The reaction mixture was stirred for 16 hours whilst warming slowly to room temperature. The reaction mixture was cooled and treated with water (10 mL) and the phases separated. The organic phase was extracted with further diethyl ether (x2) followed by dichlormnethane (x2).

The combined organic phases were dried over sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient: 17.5 to 25% acetone in cyclohexane) to afford (R)-(1-(4-fluoropheny1)-6-04-(trifluoromethyl)phenypsulfony1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-g]isoquinolin-4a-y1)(1-methy1-1H-imidazol-2-yD-(R/S)-methanol as a white powder (82 mg) LCMS (Method A, ESI): RI 2.74 min, m+H = 588.1 [01621 The following intermediates 6-9 were similarly prepared from the appropriate starting material:
Intermediate 6. (R)-(1-(4-fluorophenv1)-64(4-(trifluoromethvOnhenvbsulfony1)-4.4a.5,6.7,8-hexahydro-1H-pyrazolo[3,4-glisoquinolin-4a-v1)(thiazol-2-y1)-(R/S)-methanol IT
\)k OH 0 0 ,..._11.,.. S y N- ===,;/" "....=-= õ..e ..,..v.õ F
Fl c---5., F
101631 LCMS (Method C. ES I): RI 3.83 min, m+II = 591.0; 114 NMR (400 MHz, CDC13): 6 7.95 (t, J = 9.5 Hz, 4 F1); 7.83 (t, J - 8.6 Hz, 4 H); 7.71 (d, J = 3.2 Hz, 1 H); 7.39-7.40 (m, 2 H);
7.35 (s, 1 H); 7.30 (d, J - 3.2 Hz, 1 H); 7.21-7.22 (m, 2 H); 7.13-7.15 (m, 4 H); 7.03-7.04 (m, 2 El); 6.43 (s, .1 H); 6.28 (d, .1= 2.3 Hz, 1 H); 5.47 (d, J rr, 5.5 Hz, .1 H);
5.27 (d, .1 = 5.4 Hz, 1 H);
4.34 (d, J = 12.2 Hz, 1 El); 4.13 (t, J = 8.8 Hz, 0.5 H); 3.85 (d, J = 5.6 Hz, 1 H); 3.60-3.65 (m, 1H); 3.40 (s, 0.5 H); 3.37 (d, .1 = 6.1 Hz, 1 H); 3.15 (d, J= 16.3 Hz, 1 If);
2.74 (d, j = 12.3 Hz, 1 11); 2.67 (dd, J = 11.7, 3.8 Hz, 1 14); 2.59(d, .1= 16.7 Hz, 1 Fl); 2.38(d, .1= 11.8 Hz, 1 14); 2.19 (d, .11= 16.8 Hz, 1 H); 1.43 (s, 3 If).
Intermediate 7. (1041-(4-fluorophenvi)-6-(0-ttrifluoromethybphenvOsuifonv1)-4,4a,5,6,7,8-hexahydro-III-pyrazolo(3,4-g)isoquitiutin-4a-y1)(oxazol-4-y1)-(11.1S)-methanol . OH 00 N/I--ICTCrFF
PI
[01641 LCMS (Method A, ESI): RT 3.77 min, m+H = 575.2.
Intermediate 8. (R)-(1.-(4-fluoropheny1)-6-((4-(trifluoromethyllphenyl)sulfony1)-4,4a,5,6,7.8-hexahydro-IH-pyrazolo13.4-disoquinolin-4a-y1)(furan-2-y1)-(R/S)-methanol oil N.S 401 N/
=
\
[01651 LCMS (Method A, ESI): RI 4.04 min, m+H = 574.1.
Intermediate 9. (R)-(1-(4-fluorophenv1)-64(4-(trifluoromethOphenyl)sulfonv1)-4,4a,5.6,7.8-hexahvdro-1H-nyrazolo13,4-gliSOCIninolin-4a-y1)(thioohen-2-4-(R/S)-methanol s OH 0 p µ'=
/YII N
Fr 10166j LCMS (Method A, ES1): RT 4.11 min, m+H = 590.1.
Intermediate 10. (lb-Uri-6u tv I 1444111 swop It e n v1)-4a4R/S)-(hydroxv(pv ridin.-2-vbmethvi)-4a,5,7,8-tetrah vdro-1H-pyrazoloi3.4-dismia I noline-6(4111-carboxylate N

N/

[01671 A solution of 2-bromopyridine (182 AL, 1.82 mmol) in dry diethyl ether (10 mL) was cooled to -78 C and butyl lithium (2.5 M in hexanes, 730 i.tL, 1.82 mmol) added dropwise. The mixture was stirred for 1 hour at -78 C. A solution of (R)-tert-butyl 1-(4-fluoropheny1)-4a-formy1-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-disoquinoline-6(4H)-carboxylate (800 mg, 2 mmol) in dry diethyl ether (10 mL) was added ch-opwisc and the reaction mixture was stirred for 1 hour at -78 C. The reaction mixture was stirred and warmed to 0 C over 1 hour following which the reaction was quenched by the addition of water (10 rriL). The resultant mixture was stirred for 30 minutes then extracted with dichloromethane (x2) and the combined organic phases were dried over sodium sulfate. The solids were removed by filtration, the filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (gradient: 30-50% ethyl acetate in cyclohexane) to afford the diastereoisomeric mixture (R)-tert-butyl 1-(4-fluoropheny1)-4a-(R/S)-(hydroxy(pyridin-2-yl)methyl)-4a,5,7,8-tetrahydro-IH-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate as a straw-coloured foam (410 mg) . LCMS
(Method C, ER): RT 2.64/2.81 min, m+H = 477.3.
In I et ittediate 11. 1R)-tert-butyl 1-(4-fluoropherrvi)-42-picolinov1-4a,5,7,8-tetrahvdro-1H-pi razolo13,4-glisthaninoline-04H)-carboxylate N

N/
N 0-t= 1 01681 A solution of (R)-tert-butyl 1-(4-fluoropheny1)-4a-(R/S)-(hydroxy(pyridin-2-y1)methyl)-4a,5,7õ8-tetrahydro-111-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate (410 mg, 0.86 mmol) in dry dichloromethane (10 mL) was treated with 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxo1-3(1H)-one (547 mg, 1.29 mmol; Dess-Martin periodinane) and the reaction mixture .. was stirred for 1 hour at room temperature. The reaction mixture was cooled and treated with saturated sodium hydrogen carbonate solution (20 mL) followed by dichloromethane (10 mL).
The mixture was stirred for 10 minutes and the phases were separated. The aqueous phase was extracted with further dichloromethane (x2) and the combined organic phases dried over sodium sulfate. The solids were removed by filtration, the filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (gradient: 20-40%
ethyl acetate in cycl.ohexane) to afford (R)-tert-butyl 1.-(4-fluoropheny1)-4a-picolinoyl-4a,5,7,8-tetrahydro-IH-pyrazolo[3,4-disoquinoline-6(4H)-carboxylate as a pale yellow foam (185 mg).
LCMS (Method B, ESI): RI 4.13 min, m414. = 475.5; 1H NMR (400 MHz, CDC1.3): 6 8.68 (d, J
= 4..8 Hz, 2 H); 7.4.4-7.45 (m, 5 H); 7.15-7.16 (m., 3 H); 6.51 (s, 2 H); 2.83 (br s, 5 H); 2.49(s, 1 H); 1.43 (s, 9 H).
[0169j Alternative procedure: 2-Bromopyridine (110.0 g, 690 mmol.e) as a solution in diethyl ether (200 mL) was added to a cooled (-65 C) solution of 2.5 M n-BuLi (275 mL, 690 rnmol) in diethyl ether (200 mL). The mixture was stirred for 1 h at -70 C to -65 C. To this solution was then added a suspension of (R)-6-tert-butyl 4a-methyl 1-(4-fluoropheny1)-4a,5,7,8-tetrahydro-1 Il-pyrazolo[3,4-disoquinoline-4a,6(4H)-dicarboxylate (100.0 g, 230 mmol) in diethyl ether (1.0 L), keeping the temperature below -65 C. The resulting solution was stirred for 2 hours at -70 C to -65 C. The reaction mixture was quenched with glacial acetic acid (50 mL) and diluted with water (200 mL). The organic layer was washed with 20% aqueous sodium chloride solution (250 mt.), dried over magnesium sulphate and concentrated to give a yellow foam. The crude product was purified over silica gel (350 g, 240-400 mesh) by elution with heptanelethyl acetate (8:1 to 2:1) to give (R)-tert-butyl 1-(4-fluoropheny1)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate (109.5 g) as a yellow foam.
Intermediate 12. (11)-(1-(4-fluorophenv1)-41,4a,5,6..7,8-11exahydro-11-1-pyrazolo13,4-glisominolist-Jia-v1)(nvridin-2-vOraiethartone .7,) =-=" N

NH
Nig N-[01701 (R)-tert-butyl 1-(4-fluoropheny1)-4a-picolinoy1-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-flisoquinoline-6(4H)-carboxylate (180 mg, 0.39 mmol) was dissolved in HC1-dioxan (4 M, 4rnL) and the resultant solution was stirred vigorously at room temperature for 1.5 hours. The reaction mixture was evaporated to afford (R)-(1-(4-fluorophenyD-4,4a,5,6,7,8-hexahydro-1H-pyra2010[3,4-glisoquinolin-4a-y1)(pyridin-2-yl)methanone as a yellow solid .
LCMS (Method B, ES1): RT 0.30 and 2.01 min, m+H = 375.2.
Intermediate 13. (R)-( 64(6-chloropyridin-3-yl)sulfonv1)-1-(4-fluorophenyi)-41,4%5,6,7,8-lioiahvd ro- I 11-m razolo13.4-ggsoguinoin-4a7y1grovridin-2-vihnethanone N

\No NiTh Si S
/ I N
N CI
[01711 A solution of (R)-(1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-disoquinolin4a-y1)(pyridin-2-Amethanone in dichloromethane (2.5mL) (2.7 mL, ¨0.2 mmol) containing diisopropylamine (1741.1L, lmmoD was added to 6-chloro-pyridine-3-sulfonyl chloride (53 mg, 0.25 mmol) and diisopropylethylamine (100 4, 0.57 mmol) and the mixture stirred for 16 hours. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (gradient: 20-30% ethyl acetate in cyclohexane) to afford (R)-(6-((6-chloropyridin-3-yDsulfony1)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-y1)methanone as a white solid (85 mg). LCMS
(Method B ESI): RT 3.92 min, m+H = 550.0; 1H NMR (400 MHz, CDC13); 6 8.66 (d, .1= 2.5 Hz, 1 H); 8.61 (d, J = 4.7 Hz, 1 H); 7.85-7.86 (m, 3 H); 7.48-7.49 (m, I H);
7.42-7.43 (m, 2 H):
7.35 (d, J = 8.4 Hz, 1 H); 7.27 (s, 1 H); 7.15-7.16 (m, 211); 6.50 (s, 1 H);
5.57 (d, J = 12.4 Hz, 1 El); 4.23 (d, J = 16.9 Hz, 1 H); 3.85-3.95 (m, 1H); 2.86-2.87 (m, 3 H); 2.66 (d, J = 11.9 Hz, 1 H);
2.53 (d, J = 15.1 Hz, 1 H).
[01721 The following intermediate 14 was similarly prepared from the appropriate starting materials:
Intermediate 14. (R)-(64(6-ehloropyridin-3-vlisulfonv1)-1-(4-fluoropheny1)-4.4a.5,6.7,8-hexahvdro-1H-vvrazolof3,4-glisoauinolin-4a-v1)(thiazol-2-v1)methanone ([4 S
,s N
[01731 I..CMS (Method F, ES-API): RT 2.46 min, m+H = 555.8; 1H NMR (400 MHz, CDC13):
6 8.68 (1H, dd, J = 2.6, 0.7 Hz), 8.00 (111, d, J = 3.0 Hz), 7.89 (111, dd, J
= 8.3, 2.6 Hz), 7.69 (11-I, d, J = 3.0 Hz), 7.46-7.40 (21I, m), 7.37 (III, dd, J = 8.3, 0.7 Hz), 7.29 (1H, s), 7.20-7.14 (2II, m), 6.55 (Hi, d, J = 2.2 Hz), 5.50(111, dd, J = 12.5,2.0 Hz), 4.17(111, d, J = 16.7 Hz), 3.97-3.91 (1E1, m), 2.92-2.83 (3H, m), 2.69-2.63 (iH, m), 2.60-2.54 (11-1, m).
Intermediate 15. (R)-(1(4-fluoropheity1)-6-(14-(trifitiorornethµ 1)i) hen vOsulfonv1)-4,4a.5,6,7,8-he xa h ro- I 11-pyraz01013,4-v.liSOQUinotin-4a-v1)(5-methyl- I
3,4-oxadiazol-2-0-(RJS)-meth anoi N-N

N / I Nr-S /111 \rµi =

[01741 2-Methyl-[1,3,4]-oxadiazole (140 mg, 1.67 mmol) in dry tetrahydrofuran (5 ml) was cooled to -78 C and butyl lithium (2.5 M solution in hexanes, 6004,1.5 mmol) was added dropwise. The resultant reaction mixture was stirred for 10 minutes at -78 C.
Magnesium bromide diethyl etherate (400 mg, 1.55 mmol) was added in one portion and the mixture was warmed to -45 C over 1.5 hours where the temperature was maintained for 20 minutes. The reaction was re-cooled to -78 C and a solution of (R)-1-(4-fluoropheny1)-644-(tiff uoromethyl)phenyl)su lfonyI)-4,4a,5,6,7,8-hexahydro-IH-pyrazo I o[3,4-g]
soquinoli ne-4a-carbaldehyde (100 mg, 0.4 mmol) in dry tetrahydrofuran (5 mL) was added dropwise and the reaction mixture was stirred whilst allowing the reaction mixture to warm to -5 C slowly. The reaction mixture was treated with saturated ammonium chloride solution (6 mi.) and sufficient water to dissolve precipitated salts. The mixture was extracted with dichloromethane (3 x 10mL) and the combined organic phases were dried over sodium sulfate. The solids were removed by filtration, the filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (gradient: 50-100% ethyl acetate in cyclohexane) to afford, as a (-2:1) mixture of diastereoisomers, (R)41-(4-fluoropheny1)-6-((4-ctrifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-IH-pyrazol o[3,4-g]
isoqu inolin-4 a-yl)(5-methy1-1,3,4-oxadiazol-2-yl)-(R/S)-methanol as an off-white foam (50 mg). LCMS
(Method A., EST): RT 3.38 min, --590.4; 1H NMR (400 MHz, CDCI3): 8 8.33 (s, 0.3 -1-1);
7.96 (d, S - 8.2 Hz, 2 H); 7.85-7.87 (m, 3 El); 7.42-7.43 (m, 1 H); 7.30(s, 1 H); 7.20-7.21 (m, 2 Fl); 7.12-7.13 (m, 2.5 H); 6.43 (s, 0.4 H); 6.18 (d, J = 2.3 Hz, 1 H); 5.43 (d, J. 4.4 Hz, 1 H); 4.99 (s, 0.4 El); 4.30-4.32 (m, I H); 3.68-3.75 (in, I IT); 3.48 (d, S = 16.7 Hz, 1 H); 129 (d, J = 16.2 Hz, 0.4 H); 3.02-3.05 (m, 1 El); 2.57 (d, J = 12.0 Hz, 3 H); 2.43-2.48 (m, 2 H); 2.35-2.37 (m, 2 H); 2.20 (s, 2 El).
Intermediate 16. (11)-(1-(4-fluoronhenv1)-64(4-(trifluoromethvOnhenvDsulfonvh-4,4;1.5.6,7.8-hex ahvd ro-1.11-Dvrazolo13.4-21isoci ui noli n -4a-v1)(oxazol-2-v1)-(R/S)-m ethanol er;

0 \\i/
N I
µN
\
101751 To a solution of oxazole (99 ItL, 0.5 mmol) in dry tetrahydrofuran (2.5 mL) was added borane-tetrahydrofuran complex (1.0 M in tetrahydrofuran, 1.65 nunol, 1.65 mL) and the mixture was stirred at room temperature for 1 hour. The mixture was cooled to -78 C and butyl lithium (1.6 M solution in hexanes, 1.20 mL, 1.95 mmol) was added dropwise.
The reaction mixture was stirred for 40 minutes at -78 C. A solution of (R)-1-(4-fluoropheny1)-6-((4-(trifluoromethyl)phenyl)sulfony1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-disoquinoline-4a-carbaldehyde (250 mg, 0.5 mmol) in dry tetrahydrofuran (3 mL) was added dropwise and the reaction mixture was stirred at -78 C for 2 hours. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was poured into ethanollacetic acid mixture (95:5, \fly; 50 mL) and stirred at room temperature for 18 hours. The solvent was evaporated and the residue was dissolved in ethyl acetate (30 mL). The organic phase was washed with water (20 mL), saturated sodium bicarbonate (2 x 20 mL) and brine (20 mL). The organic phase was dried over sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient: 0-4% methanol in dichloromethane) to afford, as a mixture of diastereoisomers, (R)-(1-(4-fluoropheny1)-644-(trifluoromethypphenypsulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-y1)(oxazol-2-y1)-(RIS)-methanol as a white foam (136 mg). L.C.MS (Method A, EST): RT 3.68 min, m+H =575Ø
101761 The following intermediates 17-20 were similarly prepared from the appropriate starting material:
Intermediate 17. (R)-(1 (4-fluoro nvi)-6-(m-tolylsulfony1)-4,4 ,8 -hex ahvdro- 1H-ovrazolo 1.3 .4-gliSOCINillOiin-4a-vi)(oxazol-2-y1)-(R/S)-methanol (stk4 0 OH 0µ 0 N
N I
101771 I..CMS (Method F, ES-API): RT 2.26 min, m-i-H = 521.1.
Intermediate 18. (R)-(64(3,5-difluorophenyl)sulfonv1)-144-fluoropheny1)-4,4a.5.6,7,8-hexahydro-IH-pyrazo1o[3,4-glisoquino1in-4a-y1)(4-methoxypyridin-2-v1)-(R/S)-methano1 Me OH 0, p N F
' 111-) 101781 1.,CMS (Method F, ES-API): irr 1.70, 1.76 min, m441 -- 583.2.
Intermediate 19. ( R)-(4-ethylpyridin-2-v1)(1-(4-fluoropheny1)-64(3,4,5-tti fluorophenynsul tbnv1)-4,4a,5,6,7,8-hexah_ydro-Ili-pvrazolof.3,4-21isoquinolin-4a-y1)-(R/S)-methanol 0H 0, p N,µSi N I
µ11 101791 LCMS (Method F, ES-AP1): RT 1.97/2.10 min (mixture of diastercomers), m+H =
599.2.

Intermediate 20. (R)-(1-(4-fluoroolieny1)-6-((3.4,5-trifluorophenvI)sulfonv1)-4,4a,5,6,7,8-hexahydro- I H-nyrazolo13.441 iSOOtli n 01 i n-4a-v1)(4-methoxvnvridin-2 -yI)-(RIS)-methanol 0H 0,, /0 F
I
µ"=-=esN.1 =-=="7"."-. "`= F
c\-51 [01801 LCMS (Method F, ES-API): RT 1.90 min, m+H = 601.2.
Intermediate 21. (R)-tert-butv I 1-t4-flunrophenv1)-4a-(thiazole-2-wrbon v1)-4a45,758-t et rahvd ro-1H-Dy m01013,4-2 I is0aui noline-6(4M-ca rboxvla te (IA
= 0 N..Boc N I
sl1/41 101811 2-Bromothiazole (0.643 mL, 7.14 mmol) in dry ether (7 mL) was added to n-butyllithium (2.5 M in Hexanes) (2.92 mL, 7.31 mmol) in dry ether (5 mL) at -78 C. The reaction mixture was stirred at -78 'C for 45 minutes. A solution of (R)-6-tert-butyl 4a-methyl 1-(4-fluoropheny1)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate (1.0 g, 2.339 mmol) in dry ether (15 mL) was added dropwise and the reaction mixture was stirred for 0.5 hour at -78 C. Water (60 mL) was added and the reaction mixture was stirred at room temperature for 10 minutes. The aqueous layer was extracted with dichloromethane (3 x 75 mL). The combined organic extracts were washed with brine (100 mt.), dried over magnesium sulfate, filtered and concentrated in vacuo to give a dark orange oil. The crude product was purified by column chromatography on silica gel (gradient: 0-40% ethyl acetate in isohexane) to afford (R)-tert-butyl 1-(4-fluoropheny1)-4a-(thiazole-2-carbony1)-4a.5,7,8-tetrahydro-1H-pyrazolo[3,4-disoquinoline-6(4H)-carboxylate as an off-white solid (984 mg).
LCMS (Method F, ES-AP1): RT 2.64 inin, m+H = 480.9; 1H NMR (400 MHz, CDCI3): 8 8.06 (1H, d, J = 3.0 Hz), 7.64 (1H, s), 7.48-7.43 (2H, m), 7.31 (1H, s), 7.20-7.14 (2H, m), 6.55 (1H, s), 5.60 (1H, br s), 4.49 (1H, d, i = 15.0 Hz), 4.21 (1H, br s), 3.28-3.25 (1H, m), 2.86-2.81 (3H, m), 2.49 (1H, d, J = 14.5 Hz), 1.55 (9H, s).
101821 The following intermediates 22-30 were similarly prepared starting from the appropriate starting material:
Intermediate 22. (R)-tert-butyl 1-(4-fluorophenv1)-4a41-methyl-IH-12,4-triazole-5-carbonv1)-4a5.7,8-tetrahydro-IH-rwrazolo[3,4-glisoquinoline-6(4H)-earboxylate ,1;1-N
N,Boc N
[0183] LCMS (Method F, ES-API): RT 2.51 min, m+H = 479.3.
Intermediate 23. (R)-tert-butyl 1-(4-fluorwheny1)-4a-(pyrazine-2-earbony1)-4a.5,7,8-tetrahydro-1 H-pvrazolo f 3.4-glisoquinoline-6(4H)-carboxylate ra-7"N
N..Bec N I
[0184] LCMS (Method F, ES-API): RT 2.48 min, m+H = 476.3.
Intermediate 24. (R)-tert-butyl 1-(4-fluoropheny1)-4a45-methoxyuicolinoy1)-4a,5,7.8-tetrahydro-IH-Dyrazolo13.4-elisoauinoline-6(41-1)-earboxylate "

Boc N`
N
[01851 LCMS (Method F, ES-API): RT 2.67 min, m+H = 505.2.
Intermediate 25. (R)-tert-butyl 1-(4-fluoronhenyI)-4a-(4-methylpicolinoyI)-4a.5,7,8-tetrahvdro-IH-nyrazolof3.4-glisouuinoline-6(4H)-carboxylate , _Bac N
N
-"=:4\
[01861 LCMS (Method F, ES-API): RT 2.82 min, m+H = 489.3.
Intermediate 26. (R)-tert-butyl 4a-(4-ethylnicolinoyI)- I -(4-fluorouheny1)-4a,5,7,8-tetrahydro- I H-pyrazolof3.4-glisoquinoline-6(4H)-earboxylate Ro r NI, N
Si 101871 LCMS (Method F, ES-API): RT 3.05 min, m+11 = 503.3.
Intermediate 27. (R)-tert-butyl 1 Theny1-4a-p leo] inov1-4a,5,7,8-tetrahvdro-I li-nyrazolo [3.4-giisoquinoline-6(4H)-carboxylate N/ NA0..).
I
101881 LCMS (Method F, ES-A!'!): RT 2.65 min, m+H = 457.
Intermediate 28. (R)-tert-butyl 1-(4-fluoronhenv1)-4a-(2-(vvrrolidin-1-4isonicotinov1)-4a,5.7,8-tetrahydro-IH-pyrazolo[3.4-g]isoquinoline-6(4H)-carboxylate r I

N,Boc N I
N
[01891 LCMS (Method F, ES-API): RT 2.06 min, m+11 = 544Ø
Intermediate 29. (R)-tert-bubd 1-(4-chloropheny1)-4a-(4-(tritluoromethvilpieolinoy1)-4a.5 7 8-tetrahydro- I il-pyrazolo[3.4-4 isoquinol ine-6(41i)-earboxviate LNLO
N'Boc N
101901 LCMS (Method F, ES-API): RT 3.02 min, m+H = 559.2.
Intermediate 30. (R)-tert-butyl 4a-pieol inoyl- I -(4-(tri fluoromethyl)pheny1)-4a,5.7,8-tetrahydro-I H-nyrazolo[3.4-i.: lisoquinoline-6(4H)-carboxviate o NBoc N' N:\PI

101911 LCMS (Method F, ES-API): RT 2.90 min, m+H = 525.
Intermediate 31. (R)-(144-fluoropheny1)-4,4a15,6.7.8-hcxahvdro-11-1-ovrazolol3,4-glisoquinolin-4a-v1)(thiazol-2-y1)methanone 2,2,2-triflum-oacctatc = NH
j N
101921 A solution of (R)-tert-butyl 1-(4-fluoropheny1)-4a-(thiazole-2-carbony1)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-disoquinoline-6(4H)-carboxylate (1.0 g, 1.561 mmol) in 20%
trifluoroacetic acidldichloromethane (100 mL) was stirred at room temperature for 30 minutes.
The solvent was removed in vacuo then the crude residue azeotroped twice with toluene to give (R)-(1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-g]isoquinolin-4a-y1)(thiazol-2-y1)methanone trifluoroacetate as an orange solid (0.584 g). LCMS (Method F, ES-API): RI 1.30 min, tn+H = 381.0; 1H NMR (400 MHz, CDC13): 6 8.02 (111, d, J = 2.7 Hz), 7.78 (111, d, 1 = 2.7 11z), 7.48 (111, s), 7.46-7.41 (211, in), 7.24-7.16(211. m), 6.57 (HI, s), 4.45 (111, d, .1= 12.5 Hz), 3.86 (11, d, J = 16.2 HZ), 3.74-3.65 (2H, in), 3.34(11, d, J = 13.2 Hz), 3.12 (1H, br = 10.6 Hz), 2.89 (1H, d, .1= 16.2 Hz), 2.82 (1H, d,1 = 13.1 Hz), 2.62 (1H, d, J =
15.4 Hz).
Intermediate 32. (10-tert-butyl 1-(4-fluctropheny1)-4a-(2-(trimethvIsily1)thiazole-4-carbmw1)-4a,5,7,8-tetrahydro-IH-pyrazolo13,4-glisoquinoline-6(41)-carboxvlate MS
N
S
,0 Boc N
F
[01931 A solution of 4-bromo-2-(trimethylsilyl)thiazole (304 jil, 1.784 mmol) in dry ether (2 mL) was added to a solution of butyllithiurn (2.5 M in Hexanes) (731 IA, 1.828 mmol) in dry ether (1 mL) at -78 C. The reaction mixture was stirred at -78 C for 30 minutes. A solution of (R)-6-tert-butyl 4a-methyl 1-(4-fluoropheny1)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-disoquinoline-4a,6(4H)-dicarboxylate (250 mg, 0.585 mmol) in dry ether (5 mL) was added dropwise and the reaction mixture was stirred for 0.5 hour at -78 C then slowly warmed to -50 C over 2 hours. Water (10 mL) was added and the reaction mixture was stirred at room temperature tor 10 minutes. The aqueous layer was extracted with ethyl acetate (3 x 15 mi.). The combined organic extracts were washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give a dark orange oil. The crude product was purified by column chromatography on silica gel (gradient: 0- /0% ethyl acetate in isobexane) to afford (R)--tert-butyl 1-(4-fluoropheny1)-4a-(2-(trimethylsily1)thiazole-4-carbonyl.)-4a,5,7,8-tetrahydro- I H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate as a pale yellow foamy solid (76 mg). LCMS
(Method F, ES-API): RT 2.65 min, = 553.3.
Intermediate 33, (R)-niethvl 1-(4-11tiorophenv1)-64(3-(trifluoromethvflphenvbsulfonvb-4,4a,5,6..7õ8-11ex alivd ro- I 11-pyrazo10 3,4-glisowdnoline-4a-ca rboxy te Me0y.0 0, /0 N
j [01941 A solution of (R)-6-tert-butyl 4a-methyl 1-(4-fluoropheny1)-4a,5,7,8-tetrahydro-III-pyrazolo[3,4-disoquinoline-4a,6(411)-dicarboxylate (2.0 g, 4.68 mm.ol) in 20%
trifluoroacetie acidldichloromethane (50 mL) was stirred at room temperature for 1 hour. The solvent was removed in vacuo, azeotroping three times with toluene (-20 mL), to give a dark orange oil. The oil was dissolved in dichloromethane (50 mL) and 3-(trifluoromethyl)benzene-l-sulfonyl chloride (0.900 ml, 5.61 mmol) was added followed by diisopropylethylamine (4.09 ml, 23.39 mmol). The reaction mixture was stirred at room temperature for 20 minutes, and then solvent removed in vacuo to give a dark orange oil. The crude product was purified by chromatography on silica gel (gradient: 0-45% ethyl acetate in isohexane) to afford (R)-methyl 1-(4-fluoropheny1)-643-(trifluoromethyl)phenyl)sulfony1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-disoquinoline-4a-carboxylate (931 mg) as a pale yellow solid. LCMS (Method F, ES-API): RI
2.62 min, m+14 = 536.2.
[01951 The following intermediates 34-54 were similarly prepared from the appropriate starting material:
Intermediate 34. (R)-methvl 1-(4-fluorobhenv1)-6-(m-tolvisulfonv1)-4,4a,5.6,7,8-hexahvdro-1H-pvrazolor3,4-gliSOQUinoline-4a-carboxvIate Me0 0 14=sir-N I
I
10196] LCMS (Method F, ES-API): RI 2.52 mm, m+H = 482.2.
Intermediate 35. (R)-methyl 1-(4-fluorophenv1)-643-methoxythenvpsulfonv1)-4,4a,5.6,7,8-hexahydro-IH-pvrazolo[3,4-glisoquinoline-4a-carboxvIate Me0 0 0, 4111 OMe N I N

[01971 LCMS (Method F., ES-API): RT 2.44 min, m-+.171 = 498.

Intermediate 36. (R)-inethvi 64(3-fluoro-4-methylphenyi)suifonvi)-1-(4-fluoropheny1)-4,4a,5.6,7,8-hexahvdro-1H-Dyrazolo[3,4-disociuino1inc-4a-carboxv1ate Me0 0 0,, 01 ' N I N
[0198i 1..CMS (Method F, ES-API'): RT 2.57 min, m+1-1 = 500.
intermediate 37. (R)-rnethyll-(4-fluorophenyi)-6-(phenvIsultbny1)-4.4a.5.6,7,8-hexahydro-11-1-pyrazolo13.4-disoquinoline-4a-earboxylate Me0y0 N
sN=
101991 LCMS (Method F, ES-API): RT 2.40 min, m+H = 468.2.
Intermediate 38. (R)-methyl 64(3-chlorophenyllsulfonv11-1-(4-fluorophenv1)-4,4a.5,6,7,8-hexahydro-1H-pyrazolo 3,441isoquino1i ne-4a-carboxv late Me 000 we 40N I
[0200i 1.,CMS (Method F, ES-API): RT 2.58 min, m+H = 502.2.
Intermediate 39. (R)-methyl 1-(4-fluoropheny1)-6-tosv1-4.4a.5,6,7.8-hexahydro-IH-pyrazolo13.4-glisoquinoline-4a-carboxylate Me0 0 0, .1 ,µS
N

=
[0201.1 LCMS (Method F, ES-API): RT 2.51 min, m+11 = 482.
Intermediate 40. (R)-methyl 6-((4-tluoro-3-(trifluoromethyl)phenvI)sulfonyl)-fl 0 ropheny1)-4,4a.5.6,7.8-hexabvdro-IH-pyrazolo[3,4-glisoquinoline-4a-carboxylate o r (73 N=
102021 Using HC1 (4M solution in dioxanc) in place of trifluoroacctic acid/dichloromethanc.
LCMS (Method F. ES-API): RI 2.66 min. m+11 = 554.
Intermediate 41. (R)-methyl 1-(4-fluoropheny1)-643,4,5-trifluorophenypsulfony1)-4,4a,5,6,7,8-hexahvdro-IH-pyrazolo[3,4-disoquinolinc-4a-carboxylate rvieo 000µ
hi/ I
µ14 11111 F
[02031 Using HC1 (4M solution in dioxane) in place of trifluoroacetic acididichloromethane.
LCMS (Method F, ES-API): RT 2.59 min, = 522.1.
Intermediate 42. (R)-methvl 643-fluoro-4-(trifluoromethvilphenyl)sulfony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-disoquinoline-4a-carboxylate fs,lea0 op '---,--- F-- N 'a Nis 1 I 1 40 r_i 4i1 j) F
102041 Using HC1 (4M solution in dioxane) in place of trifluoroacetic acid/dichloromethane.
LCMS (Method F, ES-API): RI 2.88 min, m+H = 554.2.
Intermediate 43. (R)-methyl 6-(f I -ethyl- 1 H-pyrazol-4-yl)sulfony1)- I -(4-fluorophenvI)-4,4a.5,6,7,8-hexahydro- I H-pyrazolo[3..4-glisoquinoline-4a-carboxvlate Me00 0, p tµI
..,..,.=
i ., n.õ......--..õ.õ..-..N....õ...
' I j r4 N
* ) F
[02051 Using HC1 (4M solution in dioxane) in place of trifluoroacetic acidldichloromethane.
LCMS (Method F, ES-API): RT 2.38 min, m+I-1 = 486.2.
Intermediate 44. (RI-methyl 643,4-dichlorophenylIsulfony1)-1-(4-fluorophenyt)-4,4a.5,6,7,8-I 0 hexahydro-1H-pyrazolo[3,4-gjisoquinoline-4a-carboxylate ci j) s.
Me 0 0 411 N4, I N No N .----f---,=
F
[02061 Using HC1 (4M solution in dioxane) in place of trifluoroacetic acid/dichloromethane.
LCMS (Method F, ES-API): RT 2.71 min, m+H = 536.
Intermediate 45. (RI-methyl 1-(rwridin-3-y1)-643-(trifluoromethyl)phenybsulfony1)-.. 4,4a.5.6.3,8-hexahydro-1H-Dyrazolo[3,4-glisoquinoline-4a-carboxylate µCF3 N, N
[02071 Using HC1 (4M solution in dioxane) in place of trifluoroacetic acid/dichloromethane LCMS (Method F, ES-API): RT 2.24 min, mA-H = 519.
intermediate 46. (R)-methy16-(13.4-dichlorophenyl)sulfony1)- I Theny1-4.,4a.5,.627,8-hexahyd ro-1.H:pyrazQ1913.4-Ø5oRginoline-4a-carboxylate me0 0 0, N

102081 Using HC1 (4M solution in dioxane) in place of trifluoroacetic acid/dichloromethane.
LCMS (Method F, ES-API): RT 2.68 min, m-FH = 519.
Intermediate 47. (R)-methyl 643,4-difluorophenvOsulfony1)-1-(4-fluoropheny1)-4,44,5,6,7,8-hexahydro-1H-pyrazolo[3,4-glisoquinoline-4a-earboxylate Me0 0µµ 141-11 F
-N I N
[02091 Using HC1. (4M solution in dioxarie) in place of trifluoroacetic acid/dichlorornethane.
LCMS (Method F, ES-API): RT 2.48 min, m-FH = 504.
Intermediate 48. (R)-methyl 6-0.4-diehlorophpny1il1fony1)- I -(3.4-difluorophenA-4.,4a,5.6,7,8-hexahydro-1H-pyrazolo[3.,4-glisoquino line-4a-c arbox v late =,... .C1 M e0., 0 0 Lets., N" i\j0 SµN CI

sN' /
1-----.
''-----;t= F
F
[02101 Using HC1 (4M solution in dioxane) in place of trifluoroacetic acid/dichloromethane.
LCMS (Method F, ES-API): RT 2.78 min, m+1.1 = 555.
Intermediate 49. (R)-methyl 6-04-chloro-3-fluoropheny1lsu1 fony1)-1-(4-fluorophenYI)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3.4-disoquirioline-4a-carboxylate Me0 0 00 :
N...6,:):F
/

CI

F
102111 Using HC1 (4M solution in dioxane) in place of trifluoroacetic acid/dichloromethane.
LCMS (Method F, ES-API): RT 2.59 min, m-FH = 520Ø
Intermediate 50. (10-methyl 1-(4-fluoropheny1)-64( 1-methy1-1H-pyrazol-3-y1)sulfonY1)-4.4a.5.6,7,8-hexahydro-1H-pyrazolo[3.4-glisoquinoline-4a-carboxylate Me0 0 0, 0 ,µe N y-, N/ I
N NI- N
i c..-F
102121 Using HC1 (4M solution in dioxanc) in place of trifluoroacetic acid/dichloromethanc.
LCMS (Method F, ES-API): RT 2.00 mm, m-FH = 472Ø
Intermediate 51. (R)-methyl 1-(4-fluoropheny1)-64(1-methyl-IH-pyrazol-4-yl)sulfony1)-4.4a..5.,6,7,8-hexahydro-1H-nyrazolor3A-glisoquinoline-4a-carboxylate f,-...N
Me0 ,0'N¨

os.-------/
N14.---. . 0 N

F
[02131 Using HC1 (4M solution in dioxane) in place of trifluoroacetic acid/dichloromethane.
LCMS (Method F, ES-API): RT 1.99 min, m+H = 472.
Intermediate 52. (R)-methvl 6-((1..3-dimethy1-1H-pyra.zol-5-v1)sulfonv1)-1-(4-fluorophenv1)-4,4a.5.6.3,8-hexahvdro-1H-oyrazolo[3,4-glisoquinoline-4a-carboxvlate Me0 000 J
Y
N i 1 110 'NI N
-1) tr.:---I
F
102141 Using HC1 (4M solution in dioxane) in place of trifluoroacetie acid/dichloromethane.
LCMS (Mulhod F, ES-API): RT 2.23 min, in.+H - 486.2.
Intermediate 53. (R1-methyl 1-(4-fluoropheny1)-64( 1-methyl -111 -pvrazol-5-y1)sulfonyl)-4,4a,5.6.7.8-hexahydro-111-pyrazolot 3.4-Wisoquinoline-4a-carboxylate Me0 000, µe =N N. - l / N
.

[0215j Using HC1 (4M solution in dioxane) in place of trifluoroacetic acidldichloromethane.
LCMS (Method F, ES-API): RI 2.15 min, m+I-1 = 472.2.
Intermediate 54. (R)-methyl 64(1-ethyl-I H-pyrazol-5-yl)sul fony1)-1-(4-fluorophenv1)-.. 4.,4a,5õ6,7,8-hexahydro-1H-pyrazolo[3,4-glisoquinoline-4a-carboxylate Me0 0 0µ
iy /NN
[0216] Using HC1 (4M solution in dioxane) in place of trill uoroacetic acid/dichloromethane.
LCMS (Method F, ES-API): RT 2.26 min, m+H = 486.1.
N ermediate 55. (R)-tert-butvl 1-(4-fluorophenyI)-4a-(thiazo1e-5-ea rbouvI)-4a,5,7.8-to nt hydre-11-1-pvrazolo13,4-disopuinoline-6(4H }-earhoxylate N' B"
NLI
102171 2-(Trimethylsilypthiazole (285 1, 1.784 mmol) in dry ether (2 mL) was added to butyllithium (2.5 M in Hexanes) (731 !xi, 1.828 mmol) in dry ether (1 mL) at -78 C. The reaction mixture was stirred at -78 C for 30 minutes. A solution of (R)-6-tert-butyl 4a-methyl 1-(4-fluoropheny1)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate (250 mg, 0.585 mmol) in dry ether (6 mL) was added dropwise and the reaction mixture was stirred for 0.5 hour at -78 'C. Water (10 mL) was added and the reaction mixture was stirred at room temperature for 10 minutes. The aqueous layer was extracted with ethyl acetate (3 x 15 traL). The combined organic extracts were washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give an orange solid. The crude product was purified by chromatography on silica gel (gradient: 0-40% ethyl acetate in isohexane) to afford (R)-tert-butyl 1-(4-fluoropheny1)-4a-(2-(trimethylsilypthiazole-5-earbony1)-4a,5,7,8-tetrahydro-1H-pyrazolo[34-disoquinoline-6(4H)-carboxylate (88mg) as a yellow solid. LCMS
(Method F, ES-API): RI 2.38 min, m+H = 481.2.

Intermediate 56. (R)-(144-fluoronlienv1)-6-( m-tolvisullonv1)-4,4a,5.6,7.8-hexahvdro-1H-pyrazolo13,4-21iSOnninolin-4a-v1)niethanol OH 0 ..., rststµl --- '..-,='''' /
n/
)....i F
102181 Superhydride (1M solution in tetrahydrofuran, 43.2 ml, 43.2 mmol) was added slowly to a solution of (R)-methyl 144-fluoropheny1)-6-(m-tolylsulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinoline-4a-carboxylate (5.2 g, 10.80 mmol) in tetrahydrofuran (100 mL) at 0 C and stirred for 2 hours. The reaction was quenched with ammonium chloride solution (aqueous, 100 mL) and ethyl acetate (100 mL) was added. The phases were separated and the organic phase was washed with brine (100 mL), dried (sodium sulphate) and solvent removed to give a yellow oil. The crude product was purified by chromatography on silica gel (gradient: 0-80% ethyl acetate in isohexane) to afford (R)-(1-(4-fluoropheny1)-6-(m-tolylsulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)methanol (4.45 g) as a white solid.
LCMS (Maliud F, ES-API): RT 2.36 min, ni. H - 454.
102191 The following intermediate 57 was similarly prepared from the appropriate starting materials:
Intermediate 57. (R)-(64(3,5-difluorophenyl)sulfonvi)-1-(4-fluoronhenv1)-4,4a,5.6.7.8-hexahvdro-1H-pyrazolo[3,4-glisoquinolin-4a-y10)mHo o ethanol , , N - F:
,, 'N ..- -...y..--( -- /
F
[02201 LCMS (Method F, ES-API): RI 2.40 min, m-F1-1 ::: 476.2.

Intermediate 58. (R)-1-(4-fluorophenv1)-6-(m-tolvIsulfonv1)-4,4a .5.6,7,8-hexahydro-1H-pvrazo1013,4-2 I iSOCluinoline-4a-ca rba Idehvde H 00 n N "µS\'}

[0221.1 (R.)-(1-(4-Fluoropheny1)-6-(m-tolylsulfony1)-44a,5,6,7,8-hexahydro-1H-pyrazol o [3,4-g]isoquinolin-4a-Amethanol (3.5 g, 7.72 mmol) was dissolved in dichlorom.ethane (80 mL) and Dess-Martin Periodinane (5.24 g, 12.35 mmol) was added. The reaction was stirred at room temperature for 1 hour. A saturated solution of sodium hydrogen carbonate (aqueous, 50 ml) was added and the mixture was stirred for 10 minutes. The phases were separated and solvent removed to give a pale yellow solid. The crude product was purified by chromatography on silica gel (gradient: 0-80% ethyl acetate in isohexane) to afford (R)-1-(4-fluoropheny1)-6-(m-tolylsulfony1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-g]isoquinoline-4a-carbaldehyde (2.9 g) as a very pale yellow solid. LCMS (Method F, ES-API): RT 2.46 min, mf H= 452.
[0222] The following intermediates 59-61 were similarly prepared from the appropriate starting material:
Intermediate 59. (11)-64(3,5-dffluoronhenynsullonv1)-1-(4-fIuorophenv1)-4,4a,5,6,7.8-hexahvdro-IH-pvrazoloi3,4-iliiSOCIUinoline-4a-carbaldehyde 0 0_0 r N"µSi N 1 a [0223] LCMS (Method F, ES-API): RT 2.54 min, m+H = 474.2.
Intermediate 60. (R)-1-(4-fluoronheny1)-643,4,5-trifuorophenv1)sulfonyl)-4,4a.5,6.7,8-hexahydro- I H-pyrazolof 3,4-g]isoquinolinc-4a-carbaldehvde 0:.vp Ns I
102241 LCMS (Method F, ES-API): RI 2.85 mm, m-1-11-1-CH3OH (sample prepared in CH3OH, giving methanol hemiacetal) = 524.2.
Intermediate 61. (R)-tert-butyl 1-(4-fluorophenv1)-4a-(1-methyl-IH-_pvrazole-4-carbony1)-4a.5,7.8-tetrahydro-1H-vvrazolo[3,4-glisoouinoline-6(4H)-carboxvlate N
Bac N I
102251 ECMS (Method F, ES-API). RI 2.24 min, mi-F1 = 4714.2 Intermediate 62. (R)-(144-fluoronhenvb-64nt-tolvisulfonvI)-4.4a.5.6.7.8-hexahvdro-11-1-pvrazoin13A-alisonninotin-4a-v1)(nvrimidin-2-viHR/S)-methanol i OH ON
N,µS/
N
N
=
ci [02261 To a stirred solution of 2-(tributylstannyl)pyrimidine (428 I, 1.351 mmol) in dry tetrahydrofuran (5 inL) was added butyllithium (2.5 M in hexanes) (554 I, 1.384 mmol) at -78 C. The reaction mixture was stirred at -78 C for 1.5 hours. A solution of (R)-1-(4-fluoropheny1)-6-(m-tolyisulfonyl)-4,4a,5,6,7,8-hexahydro-lH-pyrazolo[3,4-g]isoquinoline-4a-carbaldehyde (200 mg, 0.443 mmol) in thy tetrahydrofitran (5 mL) was added dropwise and the reaction mixture was stirred for 1.5 hours at -78 C. Water (25 mL) was added and the aqueous Layer was extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was partitioned between acetonitrile (25 mL) and hexanes (15 mL). The hexane layer was discarded. The acetonitrile layer was concentrated in vacuo to give a pale orange oil. The crude product was purified by chromatography on silica gel (gradient: 0-100%
ethyl acetate in isobexane) to afford (R)-(1-(4-fluoropheny1)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-lH-pyrazolo[3,4-g]isoquinolin-4a-y1)(pyrimidin-2-y1)methanol (75 mg) as a colourless oil. LCMS
(Method F, ES-AP1): RT 2.27 min, m+H = 532.2.
Intermediate 63. 2-(benzvithio)-6-(trifluoromethv1)rmidine I I

[02271 To a suspension of sodium hydride (0.170 g, 4.24 mmol) in tetrahydrofuran (10 mL) was added phenylmethanethiol (0.338 ml, 2.88 mmol) dropwisc at 0 'C. The reaction mixture was stirred at 0 0C for 1 5 minutes then 2-fluoro-6-(trifluoromethyl)pyridine (0.365 ml, 3.03 mmol) was added dropwise. The reaction mixture was stirred at 0 C for 30 minutes. Methanol (1 mL) was added carefully and the reaction mixture was stirred at 0 'C for a further 10 minutes then water (5 mL) and dichloromethane (10 mL) were added. The organic layer was recovered using a phase separator cartridge then concentrated in vacuo to give 2-(benzylthio)-6-(trifluoromethyppyridine (538 mg) as a colourless oil. LCMS (Method F, ES-API): RT 2.80 min, m+H = 270.1.
Intermediate 64. 6-0rilla oromethvbpvridine-2-sulfonvl chloride CL"
o ts1,_ CF3 102281 To a suspension of 2-(benzylthio)-6-(trifluoromethyl)pyridine (580 mg, 2.154 mmol) in acetic acid (8 mL) and water (4 mL) was added N-chlorosuccinamide (1438 mg, 10.77 mmol), and the mixture was stirred at room temperature for 1 hour. Water (10 mL) was added and the mixture was extracted with dichloromethanc (2 x 10 mL). The organic extract was washed with saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give 6-(trifluoromethy1)pyridine-2-sulfonyl chloride (436 mg) as a colourless oil.
LCMS (quenching with morpholine; Method F. ES-API): RT 1.84 min, (m-tfl+molpholine-C1) =
297.1.
102291 The following intermediates 65-66 were similarly prepared from appropriate starting materials:
Intermediate 65. 2-(trifluoromethvfluvridine-4-sulfonvl chloride CLU
0' Ic...11+11 102301 LCMS (quenching with morpholine; Method F, ES-API): RT 2.03 min, (m+H+morpholine-CI) = 297.1.
Intermediate 66. 4-(trifluoromethyl)pyridine-2-sulfonvl chloride C1,11 ,CF3 [02311 LCMS (quenching with morpholine; Method F, ES-API): RT 1.85 min, (m+H-1-molpholine-C1) = 297.1.
Intermediate 67. 3-fluoro-4-arifluoromethylMenzene-1-sulfonyl chloride O'Sr:F
=====
[02321 3-Fluoro-4-(trifluoromethyl)aniline (5 g, 27.9 mmol) was dissolved in acetonitrile (10 mL). The solution was cooled to 0 C, and treated with tetrafluoroboric acid (48% aqueous solution, 6.49 ml, 41.9 mrnol) and tert-butyl nitrite (4.98 ml, 41.9 mmol).
The reaction mixture was maintained at 0 'C for 1 hour. In the meantime, a suspension of copper (I) chloride (4.15 g, 41.9 nunol) in acetonitrile (40 mL) at 0 C was saturated with sulfur dioxide gas by bubbling the gas through the suspension with vigorous stirring for 30 minutes. When the diazotization reaction was complete after 1 hour, this solution was added dropwise to the suspension of copper a) chloride, causing vigorous evolution of gas. The reaction mixture was then allowed to warm to room temperature and stirred for 1 hour, after which time it was poured onto 100 I/IL of an ice/water slurry. Diethyl ether (150 mL) was added, causing a precipitate to form, which was removed by filtration. The filtrate was washed with water (100 mL) and brine (100 mL), dried over magnesium sulfate, filtered, and concentrated in maw to give 3-fluoro-4-(trifluoromethyl)benzene-1-sulfonyl chloride (6.62 g) as an orange oil. LCMS
(quenching with morpholine; Method F, ES-API): RT 2.25 min, (m-1 l+morpholine-CD= 314.1.
Intermediate 68. (R,Z)-2-tert-butvl 8a-niettiv1 7-(hvdroxvmethviene)-6-oxo-3,4,6,7,8,8a-hexahvdroisoutiinoline-2,8a(11-1)-dicarboxvlaie N,Boc HO s=-=

102331 Lithium hexamethyldisilazide (12.93 ml, 12.93 mm.ol) was added to diethyl ether (20 ad) at -78 'C. (R)-2-tert-butyl 8a-methyl 6-oxo-3,4,6,7,8,8a-hexahydroisoquinoline-2,841H)-dicarboxylate (W02005087769) (1.0 g, 3.23 mmol) in ether (5 mL) was added followed by the addition of 2,2,2-trifluoroethyl formate (2.51 ml, 25.9 mmol) after 20 minutes. The reaction was stirred at -78 C for 2 hours then allowed to slowly warm to room temperature.
1M hydrochloric acid (8 mL) was added, followed by water (10 mL) and ethyl acetate (10mL). The organic phase was separated, washed with brine, dried (magnesium sulfate) and solvent removed to give (R,Z)-2-tert-butyl 8a-methyl 7-(hydroxymethylenc)-6-oxo-3,4,6,7,8,8a-hexahydroisoquinoline-2,841H)-dicarboxylate (1.09 g) as a yellow oil. LCMS (Method F, ES-API): RT
1.99 min, m-H
"336.
Intermediate 69. (R)-6-tert-butvl cla-methvl 1-phenvI-4a,5,7,8-t.etrahvdro-1H-pyrazolo13,4-glisoquinoline-4a,6(411 )-dicarboxvlate Me0 0 N_Boc N I
[02341 (R,Z)-2-tert-buty1 8a-methyl 7-(hydroxymethylene)-6-oxo-3,4,6,7,8,8a-hexahydroisoquinoline-2,8a(IH)-dicarboxylate (1.09 g, 3.23 mmol) was suspended in acetic acid (20 rol,), and sodium. acetate trihydrate (0.265 g, 3.23 mmol) and phenylhydrazine (0.318 ml, 3.23 mmol) were added. The reaction mixture was stirred at room temperature for 30 minutes, then water (20 ml.,) and dichloromethane (20 mI,) were added and the phases were separated via a phase separator. The solvent was removed to give an orange oil. The crude product was purified by chromatography on silica gel (gradient: 0-50% ethyl acetate in isohexane) to afford (R)-6-tert-butyl. 4a-methyl 1-pheny1-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-.. 4a,6(4H)-dicarboxylate (694 mg) as a pale yellow solid. LCMS (Method F, ES-API): RT 2.48 m+H. = 410.
[02351 The following intermediates 70-73 were similarly prepared from appropriate starting materials:
Intermediate 70. (R.)-6-tert-butyl 4a-methyl 1-(pvridin-3-y1)-4a,5,7,8-tetrahydro- I H-py raze soquinol ine-4a.6(4H)-dicarboxy late Me() 0 N' But;
N I
N
[02361 LCMS (Method F, ES-AP1): RT 2.03 min, m+11 411 Intermediate 71. tR 1-6-tert-butv 1 4a-methyl 1 -(3,4-difluoropheny1)-4a,5 ,7.8-tetrahydro- 1 1-1-pyrazolof3.4-alisoquinotine-4a.6(4I11-dicarboxylate Me0 0 N,Boc N I
=
[02371 LCMS (Method F, ES-API): RT 2.58 min, in-FEI 446.
Intermediate 72. (R)-6-tert-butyl 4a-methyl 1-(4-ehloropheny1)-4a5,7.8-tetrahydro-1H-mazolo13.4-e1isoattinoline-4a.6(4H)-dicarboxylate Me0 0 N.Boc N I
If [02381 1...C,A4S (Method F, ES-AP1): RT 2.65 min, m-I-H 444.2.
Intermediate 73. (R)-6-tert-butv14a-methyl 1-(4-(trifluoromethyl)pheny1)-4a..5.7.8-tetrahydro-EI -pyrazo lo[3.1-. disoqui nol ne-1 a,6('l 14)-di carboxv I ate Me0 0 N,Boc N I
st,4 If I 0 [02391 LEMS (Method F, ES-API): RT 2.76 min, m+I-1= 478.
Intermediate 74. 4-(benzyithio)-2-fflitluoromethvinmidine e), 02401 4-Chloro-2-(trifiuoromethyl)pyridine (141 1.11, 1.102 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (199 p.1, 1.322 mmol), and phenylmethanethiol (129 pl, 1.102 mmol) were dissolved in dry dimethylformamide (2 mL). The reaction mixture was heated at 100 C in a microwave for 30 minutes, then partitioned between ether (25 mL) and water (25 mL). The aqueous layer was extracted with ether (2 x 25 mL) and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give a pale yellow oil.
The crude product was purified by chromatography on silica gel (gradient: 0-30% ethyl acetate in isohexanc) to afford 4-(benzylthio)-2-(trifluoromethyl)pyridine (224 mg) as a colourless oil.
LCMS (Method F, ES-API): RT 2.79 min, m-FH = 270.1.
Intermediate 75. (R)-(144-fluoronhenv1)-64(3.4,5-trilluorophenvl)sulfonv1)-4,4a,5,6,7,8-hexahvdro-111-ovrazolo13.4-glisoctilinan-4a-yllmethanot ,()H 0 0 N1"==F
[02411 To a solution of (R)-methyl 1-(4-fluorophenyl)-6-((3,4,5-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-lH-pyrazolo[3,4-disoquinoline-4a-carboxylate (1.0 g, 1.918 mmol) in anhydrous dichloromethane (30 mL) at -78 C under a nitrogen atmosphere was added diisobutyl aluminium hydride (DIBAL-H) (I M in Heptane) (7.67 ml, 7.67 mmol) dropwisc over 10 minutes. The reaction mixture was stirred at -78 C for 1 hour. Water (10 mL) was then added and the reaction mixture stirred at -78 C for 5 minutes, then warmed to room temperature over 15 minutes. The solution was partitioned between ethyl acetate (150 mL) and Rochelle's salt (150 mL). The organic layer was washed with Rochelle's salt (150 mL), brine (100 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give an off white solid. The crude product was purified by chromatography on silica gel (gradient: 0-90% ethyl acetate in isohexane) to afford (R)-(1-(4-fluoropheny1)-64(3,4,5-trifiuorophenyl)sulfony1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-disoquinolin-4a-y1)methanol (680 mg) as a white solid. LCMS
(Method F, ES-API): RT 2.58 min, m+11 = 494.2.

Intermediate 76. 2-(henzvithio)-4-(trifluoromethvi)pyridine I

it [02421 To a solution of phenylmethanethiol (356 jil, 3.03 mmol.) and 2-fluoro-(trifluoromethyl)pyridine (369 ftl, 3.03 mmol) in dimethylforrnamide (5 mL) was added potassium carbonate (628 mg, 4.54 mmol). The reaction mixture was stirred at 60 C for 2 hours, then cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution (20 mL), brine (20 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give a pale yellow oil. The crude product was purified by chromatography on silica gel (gradient: 0-20% ethyl acetate in isohexane) to afford 2-(benzy1thio)-4-(trifluoromethyOpyridine (510 mg) as a colourless oil. LCMS
(Method F, ES-API): RT 3.04 min, m-i-1-1 '70.1.
Intermediate 77. 4-bromo-2-(pvrrolidin-1 -v1)pyridine \
Br 102431 2,4-Dibromopyridine (1.0 g, 4.22 mmol) was dissolved in ethanol (40 mL) and pyrrolidine (1.733 ml, 21.11 mm.ol) was added. The reaction mixture was stirred at 70 C for 20 hours. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo to give a pale yellow solid. The crude product was purified by chromatography on silica.
gel (gradient: 0-80% ethyl acetate in isohexane) to afford 2-bromo-4-(pyrrolidin-1-yl)pyridine .. (460 mg) as a white solid, and 4-bromo-2-(pyrrolidin- 1 -yl)pyridine (260 mg) as a white solid.
LCMS (Method F, ES-API): RT 0.79 min, m+H = 227.1/229.1.
Intermediate 78. (R)-(144-fluoronhenv1)-4,48,5,6.7.8-hexahvd ro- I 1.1-o-vrazolo l34-g1isoquinolin-4a-vl)(4-(trif1uoromethvI)iividin==2--etanoiic i )i0 N
Ni H
[0244] (R)-tert-butyl 1. -(4-fluoropheny1)-4a-(4-(trifluoromethyl)picolinoy1)-4a,5,7,8-tetrahydro-IH-pyrazolo[3,4-g] isoquinoline-6(4H)-carboxylate (2 g, 2.65 mmol) was dissolved in a solution of Ha in dioxane (4M) (13.27 ml, 53.1 mmol) and the reaction mixture was stirred at room. temperature for 45 minutes. The solvent was removed in vacuo to give an orange gum..
This was treated with a mixture of 10% methanol (containing 1% of ammonia)/dichlorom.ethane until complete dissolution of the gum, then the solvent was removed in vacuo to give an orange solid. The crude product was purified by chromatography on silica gel (gradient: 0-10%
methanol (containing 1`)/0 of ammonia) in dichloromethane) to give (R)-(1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(4-(trifluoromethyl)pyridin-2-y1)methanone (810 mg) as a pale orange solid. LCMS (Method F, ES-API): RT 1.41 min, m+II =
443.2.
Intermediate 79. 1.-methv1-6-oxo-1.6-dibvdronvridine-3-sulfonic acid. ammonium salt ts."14"1 0 [0245j Chlorosulphonic acid (2 ml, 30.1 mmol.) was added cautiously dropwise by pipette over 5 minutes to stirred neat 1-methylpyridin-2(1171)-one (8.09 ml, 82 mmol) and the resulting viscous solution was stirred at 50 C for 40 hours. The cooled solidified reaction mixture was then added cautiously to water (I 00m1), giving a clear brown solution. This solution was concentrated in vacuo to 40m1, then made basic with concentrated ammonia solution, and washed with dichloromethane (6x 100m1). The aqueous phase was then evaporated to give a brown slurry which was triturated in methanol and filtered. The filtrate was evaporated to give 1-methyl-6-oxo-1,6-dihydropyridine-3-sulfonic acid, ammonium salt (3 g) as a brown solid. LCMS
(Method F, ES-API): RT 0.46 min, m-H = 188Ø
Intermediate 80. (R)-methyl 6(('3.5-difilEoro-4-methox.k phenvI)sulfonv1)-1.-(4-11norot)heny0-4,4a,5.6,7.8-11exabvd ro-111-1)vrazolo13.4-0isott tiinoline-4a-carboxvia1e MeC. 0õo F
N-OMe 102461 Jo a solution of (R)-methyl 1-(4-fluoropheny1)-6-((3,4,5-trifluorophenyl)sulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinoline-4a-carboxylate (150 mg, 0.288 mmol) in dimethyl sulphoxide (4 rnL) was added sodium methoxide (25% in methanol) (65.8 0,1, 0.288 mmol) dropwise. The reaction mixture was stirred at room temperature for 1 hour, then allowed to stand at room temperature overnight. The crude product was purified by column chromatography on silica gel (gradient: 0-50% ethyl acetate in isohexane) to afford (R)-methyl 6-03,5-difluoro-4-methoxyphenyl)sulfony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-disoquinoline-4a-carboxylate (150 mg) as a pale yellow solid.
LCMS (Method F, ES-API): RT 2.51 min, in-I-11 = 534.2.
Intermediate 81. (R)-tert-butv11-(4-fluoronhenv1)-4a-(R/S)-thydroxv(1-methyl-1H-Dvrazol-4-vflmeth v11-4a.5.7.8-tetrahvdrn-1H-Dvrazolo13.4-21isoauinoline-6(41-1)-carboxviate Ng 1 F

[02471 To a solution of n-butyl lithium (2.5 M in Hexanes) (312 p.1, 0.780 mmol) in tetrahydrofuran (2 mL) was added 4-iodo-1-methy1-1H-pyrazole (157 mg, 0.755 mmol) in tetrahydrofiffan (1 mL) at -78 C. The mixture was stirred at this temperature for 1 hour, then a solution of (R)-tert-butyl 1 -(4-fluoropheny1)-4 a-formy1-4a,5,7,8-tetrahydro-1H-pyrazolo [3,4-g]isoquinoline-6(4H)-carboxylate (100 mg, 0.252 mmol) in tetrahydrofuran (1 mL) was added dropwise to the reaction mixture. The mixture was stirred at this temperature for 30 minutes.
Water (6 mL) and dichlororriethane (8 mL) were added and the phases were separated using a phase separator eartrigde. The solvent was removed in vacuo to give an orange oil.
102481 A second reaction was performed with inverse addition of n-butyl lithium. To a solution of 4-iodo-l-methyl-1H-pyrazole (157 mg, 0.755 mmol) in tetrahydrofuran (2 mL) was added n-butyl lithium (2.5 M in Hexanes) (312 p.1, 0.780 mmol) at -78 C. The mixture was stirred at this temperature for 1 hour, then a solution of (R)-tert-butyl. 1-(4-fluoropheny1)-4a-formy1-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-disoquinoline-6(4H)-carboxylate (100 mg, 0.252 mmol) in tetrahydrofuran(1 mL) was added dropwise to the reaction mixture. The mixture was stirred at this temperature for 30 minutes. Water (6 mL) and dichloromethane (8 mL) were added and the phases were separated using a phase separator cartrigde. The solvent was removed in vacuo to give an orange oil, with a similar composition to the previous reaction product according to LC/MS analysis.
[02491 Both reaction products were combined and purified by column chromatography on silica gel (gradient: 0-100% ethyl acetate in isohexane) to afford (R)-tert-butyl 1-(4-fluorophenyl.)-4a-(hydroxy(1-methyl-1 H-pyrazol-4-yl)methyl)-4a,5,7,8-tetrahydro-IH-pyrazolo[3,4-disoquinoline-6(4H)-carboxylate (41 mg) as a pale orange gum.
LCMS (Method F. ES-AP1): RI 2.21 min, m+-H = 480.2.
Intermediate 82. ((R)-tert-butyl 1-0-fluorontienvi)-4a44-(trifluorometityt)pieolinov1)-4a,5,7,8-tetrahvd ro-1H-Dvrazolof 3,4-0 isoqui noline-6(4H)-earboxviate)) CF-NBoc N, I
411.
[0250] A solution of 2-bromo-4-(trifluoromethyl)pyridinc (2.344 ml, 18.95 mmol) in dry cthcr (15 mL) was added dropwise over 15 minutes to a solution of isopropylmagnesium chloride (2M, 9.47 ml, 18.95 mmol) in dry ether (30 mL) at 0 C, during which the solution darkened to a brown colour. After stirring at 0 C for a further 45 minutes a solution of (R)-6-tert-butyl 4a-methyl 1-(4-fluorophenyl.)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g] isoquinoline-4a,6(411)-dicarbox.ylate (2.7 g, 6.32 mmol) in dry ethertetrahydrofuran (4:1, 30 rnL
total) was added dropwise over 20 minutes at 0 C. The resulting dark coloured solution was stirred at 0 C for 20 minutes, then stirred at room temperature for a further 2 hours. The reaction mixture was diluted with ice/water (20 mL), acidified with. 1M HCI (40 mL) and extracted with ethyl acetate (100 mL). The organic phase was washed sequentially with water (50 mL), saturated sodium hydrogen carbonate solution (50 mL) and brine (30 mL), dried (magnesium.
sulphate), filtered and evaporated in vacuo to give a brown gum. This was dissolved in acetonitrile (50 mL), 1M
HC1 (10 mL) was added, and the solution stirred for 2 hours at room temperature. Ethyl acetate (150mL) was added and the organic phase washed sequentially with brine (30 mL), saturated aqueous sodium hydrogen carbonate (50 mL) and further brine (30 mi.). The organic phase was then dried (magnesium sulphate), filtered and evaporated in vacuo.
[0251] The residual brown gum was purified twice by column chromatography on silica gel (gradients: 0-10% ethyl acetate in dichloromethane, and 0-30% ethyl acetate in isohexane) to give (R)-tert-butyl 1-(4-fluoropheny1)-4a-(4-(trifluoromethyppicolinoy1)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate (2.65 g) as a light brown foam.
1_12MS (Method F, ES-API): RT 2.91 min, in+H = 543.
Intermediate 83. ((R)-tert4mtvl 144-11u0r001tenv1)-42-(thiazole-4-carbottv1)-4a,5,7.8-tet rah vilro-1H-Dvrazolo13.4-mlisoquinoline-6(4H)-carboxs late) N"
NBoc N I
41k [02521 A suspension of isopropylmagnesitun chloride (2M in tetrahydrofuran, 1.755 ml, 3.51 mmol) in dry ether (4.5 mL) at 0 C was treated dropwise with a solution of 4-bromo-2-(trimethy1si1yl)thiazo1e (0.829 g, 3.51 mmol) in dry ether (2.5 mL) and the resulting suspension stirred at 0 C for 1 hour. The suspension was then treated dropwise with a solution of (R)-6-tert-butyl 4a-methyl 1-(4-fluoropheny1)-4a,5,7,8-tetrahydro-11-1-pyrazolo[3,4-E]isoquinoline-4a,6(4M-dicarboxylate (0.5 g, 1.17 mmol) in dry ethertetrahydrofuran (4:1, 5 mr, total volume) and the resulting suspension stirred at 0 C for 15 minutes. The reaction mixture was then allowed to warm, to room temperature, and the solution stirred for a further 3 hours. The reaction mixture was cooled to 0 C, and ice water (50 mL) added dropwise. The aqueous layer was extracted with ethyl acetate (3 x 50 ml.,) and the combined organic extracts washed with brine (50 mL) and dried over magnesium. sulphate. The solvent was removed to give an orange oil.
This was dissolved in acetonitrile (12 mL) and treated dropwise with 1M
aqueous HC1 (1171 p.1, 1.171 mmol.) and the resulting solution stirred at room temperature for 1.5 hours. The reaction was diluted with ethyl acetate (150 mL) and washed sequentially with brine (50 mL), saturated aqueous sodium hydrogen carbonate solution (50 mL), and further brine (50 mL).
The organic layer was dried over magnesium sulphate and the solvent removed. The crude product was purified by column chromatography on silica gel (gradient: 5-95% ethyl acetate in isohexane) to afford (R)-tert-butyl 1-(4-fluoropbeny1)-4a-(tbiazole-4-carbony1)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-flisoquinoline-6(4H)-carboxylate (238 mg) as a pale yellow gum.
LCMS (Method F, ES-API): RT 2.55 mm, = 481.2.
Intermediate 84. 4-(benzvithio)-1111-1,2,3-triazolle s 102531 Benzyl bromide (11.79 ml, 99 mmol) was added dropwise to a solution of sodium 1H-1,2,3-triazole-5-thiolate (12.2 g, 99 nunol) in ethanol (100 mi.,) at 0 C. The reaction mixture was allowed to warm to room temperature and stirred for 20 minutes. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (100 mL), brine (100 mi.) and dried (sodium sulphate). The solvent was removed to give 4-(benzylthio)-1H-1,2,3-triazole (16.9 g) as a white solid. LCMS (Method F, ES-API): RT 1.66 min, m+H = 191.9; 1H NMR. (400 MHz, CDC13): 6 9.72 (1H, v br s), 7.47 (1H, s), 7.30-7.21 (5H, m), 4.12 (2H, s).
Intermediates 85. Methylated Triazole 85a 4-(benzylthio)-2-methy1-2H-1,2,3-triazole 0.=
"µC..
85b 5-(be.nzylthio)-1-methy1-114-1,7.3-tria7ole 401 S, 85c 4-(benz-ylthio)-1-methyl-IH-1,2,3-triazolc i I 1 102541 lodomethane (2.409 ml, 38.7 mrnol) was added dropwise to a mixture of 4-(benzylthio)-1H-1,2,3-triazole (3.7 g, 19.35 mmol) and potassium carbonate (5.88 g, 42.6 mmol) in N,N-dimethylformamide (40 mL) at 0 'C. The reaction was then allowed to warm to room temperature and stirred for 1 hour. Water (40 rnL) and ethyl acetate (40 mL) were added and the phases separated. The organic phase was washed with water (2 x 40 mL), brine (40 mL), dried (sodium sulphate) and solvent was removed to give a yellow oil. The crude product was purified by column chromatography on silica gel (gradient: 0-100% ethyl acetate in isohexane) to afford three fractions:

[02551 Fraction 1 (1.61 g) as a colourless oil. LCMS (Method F, ES-API): RT
2.05 min, m+H
= 206; 1H NMR (400 MHz, DMSO-d6): 6 7.68 (1H, s), 7.35 - 7.19 (5H, m), 4.18 (2H, s), 4.11 (3H, s).
102561 Fraction 2 (816 mg) as a pale yellow oil. LCMS (Method F, ES-API): RI
1.79 min, m+H = 206; 1H NMR (400 MHz, DMSO-d6): 6 7.71 (1H, s), 7.36 - 7.23 (3H, m), 7.22 - 7.14 (2H, m), 4.09 (2H, s), 3.73 (3H, s..).
1.02571 Fraction 3 (883 mg) as a pale yellow oil. LCMS (Method F, ES-API): RI
1.68 min, m+H = 206; 1H NMR (400 MHz, DMSO-d6): 6 8.02 (1H, s), 7.34 - 7.19 (5H, m), 4.12 (2H, s), 4.00 (3H, s).
.. 102581 The following intermediates 86-88 were similarly prepared from appropriate starting materials:
Intermediates 86. Ethylated Ttiazole 86a 4-(benzylthio)-2-ethyl-2H-1,2,3-triazole 411 SsN
, 86b 5-(benzylthio)-1-ethy1-111-1,2,3-triazole =S rsi s I ,N
-N
86c 4-(benzy1thio)-1-ethy1-1H-1,2,3-triazole µ:NI
102591 Fraction 1: LCMS (Method F., ES-API): RI 2.24 min, m+H = 220; 1H NMR
(400 .. MHz, DMSO-d6): 67.69 (1H, s), 7.32 - 7.21 (5H, m), 4.39 (2H, q, i = 7.3 Hz), 4.18(2H, s), 1.40 (3H, t, J = 7.3 Hz).

[02601 Fraction 2: LCMS (Method F, ES-API): RI 1.96 min, m+H = 220; 1H NMR
(400 MHz, DMSO-d6): 8 7.74 (11-1, s), 7.32 - 7.24 (3H, m), 7.21 - 7.16 (211, m), 4.13 (2H, q, J = 7.3 Hz), 4.12 (2H, s), 1.23 (3H, t, J = 7.3 Hz).
[02611 Fraction 3: LCMS (Method F, ES-API): RT 1.85 min, m+H = 220; 1H NMR
(400 MHz, DMSO-d6): 6 8.07 (1H, s), 7.31 - 7.19 (5H, m), 4.33 (2H, q, i = 7.3 Hz), 4.11(211, s), 1.38 (3H, t, J = 7.3 Hz).
Intermediates 87. Pronviated Triazole 87a 4-(benzylthio)-2-propy1-2H-1,2,3-triazole 87b 5-(benzy1thio)-1-propy1-1H-1,2,3-triazole 1.1 =
, N
87c 4-(benzylthi o)-1-propy1-1H-1,2,3-triazo le N
[02621 Fraction 1: LCMS (Method F., ES-API): RI 2.36 min, m+H = 234.2; 114 NMR
(400 MHz, DMSO-d6): 6 7.69 (11-1, s), 7.28-7.27 (411, in), 7.25-7.20 (111, m), 4.32 (211, t, J = 7.0 Hz), 4.18 (2H, s), 1.83 (2H, sext, J = 7.0 Hz), 0.78 (3H, t, J = 7.0 Hz).
[02631 Fraction 2: LCMS (Method F, ES-API): RI 2.08 min, m+H ¨ 234.2; 111 NMR
(400 MHz, DMSO-d6): 3 7.74 (1H, s), 7.38-7.12 (5H, m), 4.13 (2H, s), 4.06 (2H, t, J
= 7.0 Hz), 1.66 .. (2H, sext, J = 7.0 Hz), 0.74 (3H, t, J = 7.0 Hz).
102641 Fraction 3: LCMS (Method F, ES-API): RT 2.01 min, m+H = 234.2; 1H NMR
(400 MHz, DMSO-d6): 6 8.04(111, s), 7.29-7.19(511, m), 4.26(211, t, J = 7.0 Hz), 4.10(211, s), 1.77 (2H, sext, J = 7.0 Hz), 0.78 (3H, t, J = 7.0 Hz).
Intermediates 88. Isonronvlated Triazoie 88a 4-(benzylthio)-2-isopropyl-2H-1,2,3-triazole 88b 5-(benzylthio)-1-isopropy1-1H-1,2,3-triazole Ci SN, Ns I , N
N
88c 4-(benzylthio)-1-isopropy1-1H-1,2,3-triazok In'tµi 102651 Fraction 1: LCMS (Method F, ES-AP1): RT 2.41 min, m+H = 234; 1H NMR
(400 MHz, DMSO-d6): 8 7.67 (1H, s), 7.31-7.21 (5H, m), 4.76 (1H, scpt, J = 6.7 Hz), 4.17 (2H, s), 1.44 (6H, ci, J - 6.7 Hz).
102661 Fraction 2: LCMS (Method F, ES-API): RT 2.09 min, m+H = 234; 1H NMR
(400 MHz, DMSO-d6): 6 7.77 (1H, s), 7.32-7.12 (5H, m), 4.60 (1H, sept, .1= 6.7 Hz), 4.11 (2H, s), 1.29 (6H, d, J = 6.7 Hz).
[02671 Fraction 3: LCMS (Method F, ES-AP1): RT 1.99 min, m+H = 234; 1H NMR
(400 MHz, DMSO-d6): 8 8.10 (1H, s), 7.30-7.18 (5H, m), 4.76 (1H, sent, J 6.7 Hz), 4.10 (2H, s), 1.43 (6H, d , = 6.7 Hz).
Intermediates 89. Preparation of Sulfonvl Chloride 2-methy1-2H-1,2,3-triazole-4-sulfonyl 89a chloride sN-1-methyl-IH-1,2,3-triazole-5-sulfonyl 89b chloride C102S, N
89c 1-methyl-1H-1,2,3-triazole-4-sulfonyl chloride [02681 Sulfonyl chlorides of Fractions 1, 2 and 3 from Intermediate 85 were prepared according to the following preparations:
102691 Preparation I, Sulfonyl Chloride of Intermediate 85 Fraction I: N-chlorosuceinimide (3.38 g, 25.3 rrunol) was added to a solution of Intermediate 85 Fraction 1 (1.3 g, 6.33 mrnol) in acetic acid (32 mL) and water (16 mL) and stirred at room temperature for 1 hour. Water (40 mL) was added and the mixture was extracted with ethyl acetate (40 mL). The organic phase was washed with saturated aqueous sodium hydrogen carbonate solution (40 mL), brine (40 mL), dried (magnesium sulfate), and solvent removed to give Preparation 1 (1.35 g) as a pale yellow oil. LCMS (Method F, ES-API; quenching into morpholine): RT 1.09 min, m+morpholine-C1=
233.1; 1H NMR (400 MHz, CDCI3): 8 8.11 (1H, s), 4.36 (3H, s).
[02701 Preparation 2, Sulfonyl Chloride of Intermediate 85 Fraction 2:
Chlorine gas was bubbled through a solution of Intermediate 85 Fraction 2 (200 mg, 0.974 rnmol) in dichloromethane (15 mL) and water (3 mL) for 2 minutes at 0 C then the reaction mixture was stirred at 0 C for a further 5 minutes. Water (10 mL) was added and the mixture was extracted with dichlorom.ethane (10 mi.). The organic phase was dried over magnesium sulfate, filtered and concentrated in maw to give Preparation 2 (317 mg) as a colourless oil.
LCMS (Method F, F.S-APT; quenching into morpholine): RT 1.17 min, m+morpholine-C1= 7311; 1 TT
NMR (400 MHz, CDC13): 6 8.27 (1H, s), 4.40 (3H, s).
[02711 Preparation 3, Sulfonyl Chloride of Intermediate 85 Fraction 3: N-chlorosuccinimide (2.60 g, 19.49 mmol) was added to a solution of intermediate 85 Fraction 3 (1.0 g, 4.87 mmol) in acetic acid (26 ME.) and water (13 mL) and stirred at room temperature for 2 hours. Water (40 mL) was added and the mixture was extracted with ethyl acetate (40 mL). The organic phase was washed with saturated aqueous sodium hydrogen carbonate solution (3 x 40 mL), brine (40 mL), dried (magnesium sulfate), and solvent removed to give Preparation 3 (810 mg) as a colourless oil. LCMS (Method F, ES-API; quenching into morpholine): RI 0.86 min, m+morpholine-C1,...
233.1; 1H NMR. (400 MHz, CDC:13): 8 8.22 (1H, s), 4.25 (3H, s).
[0272] The following intermediates 90-92 were similarly prepared from appropriate starting materials:
Intermediates 90. Preparation of Sulfonvl Chloride I l I

2-ethyl-211-1,2,3-triazole-4-sulfonyl C102S.,,c N, 90a N--chloride 90b 1-ethyl-11-1-1,2,3-triazok-5-sulfonyi chloride ,N
1-ethyl-1H-1,2,3-triazole-4-sulfonyl II '11 90c N
chloride 102731 Preparation 1, Sulfonyl Chloride of Intermediate 86 Fraction 1: LCMS
(Method F, ES-API; quenching into morpholine): RT 1.37 min, m+morpholine-C1 ¨ 247; 114 NMR
(400 MHz, CDCI3): 8 8.11 (1H, s), 4.62 (2H, q, J = 7.4 Hz), 1.66 (3H, t, J = 7.4 Hz).
[02741 Preparation 2, Sulfonyl Chloride of Intermediate 86 Fraction 2: LCMS
(Method F, ES-API; quenching into morpboline): RT 1.37 mill, m+morpholine-C1= 247; 1H NMR
(400 MHz, CDC13): 8 8.27 (1H, s), 4.75 (2H, q, J = 73 Hz), 1.70 (3H, t, J = 7.3 Hz).
[02751 Preparation 3, Sulfonyl Chloride of Intermediate 86 Fraction 3: LCMS
(Method F, ES-API; quenching into morpholine): RT 1.44 min, m+morpholine-C1= 247; 1H NMR
(400 MHz, CDCI3): 8 8.23 (1H, s), 4.56 (2H, q, J = 7.4 Hz), 1.67 (3H, t, J = 7.4 Hz).
Intermediates 91. Preparation of Sulfonyl Chloride 2-propy1-2H-1,2,3-triazole-4-sulfonyl 91a N--' chloride 1 b 1-propy1-1H-1,2,3-triazole-5-sulfonyl C102S
N

chloride 91c 1-propy1-1H-1,2,3-triazole-4-sulfonyl chloride [02761 Preparation 1, Sulfonyl Chloride of Intermediate 87 Fraction 1: LCMS
(Method F, ES-API; quenching into morpholine): RT 1.62 min, m+morpholine-CI = 261.2; 1H NMR
(400 MHz, CDC13): 68.11 (1H, s),4.53 (2H, t, J = 7.1 Hz), 2.08(211, sext, J = 7.1 Hz), 0.98 (3H, t, J= 7.1 Hz).
[02771 Preparation 2, Sulfonyl Chloride of Intermediate 87 Fraction 2: LCMS
(Method F, ES-API; quenching into morpholine): RT 1.58 min, m+morpholine-Cl. = 261.1; 1H NMR
(400 MHz, CDC13): 68.27 (1H, s), 4.68-4.64 (2H, m), 2.12 (2H, sext, J = 7.1 Hz), 1.05 (3H, t, J= 7.1 Hz).
102781 Preparation 3, Sulfonyl Chloride of Intermediate 87 Fraction 3: LCMS
(Method F, ES-API; quenching into morpholine): RT 1.38 min, m+morpholine-CI = 261.2; 1H NMR
(400 MHz, CDC13): 6 8.21 (1H, s), 4.46 (2H, t, J = 7.1 Hz), 2.04(211, sext, J = 7.1 Hz), 1.02(311, t, J = 7.1 Hz).
Intermediates 92. Preparation of Sulfonyl Chloride 92a cio,s N
2-isopropyl-2H-I,2,3-triazole-4-sulfonyl chloride '1%1' 92b 1-i sopropy1-1H-1,2,3-triazole-5-sulfonyl CIO S
chloride 2 1-isopropyl-1H-1,2,3-triazole-4-sulfonyl I `stv 92C chloride ---[0279] Preparation 1, Sulfonyl Chloride of Intermediate 88 Fraction 1: LCMS
(Method F, ES-API; quenching into morpholine): RT 1.64 min, m+morpholine-CI =261; 1H NMR
(400 MHz, CDC13): 67.62 (IF!, s), 4.76 (I scpt., J = 6.7 Hz), 1.46 (6H, d, J = 6.7 Hz).
[0280] Preparation 2, Sulfonyl Chloride of Intermediate 88 Fraction 2: LCMS
(Method F, ES-API; quenching into morpholine): RT 1.57 min, m+morpholine-C1 = 261; 1H NMR
(400 MHz, DMSO-d6): 67.60 (1 s), 5.25 (III, sept., J = 6.7 Hz), 1.49 (6H, d, J = 6.7 Hz).

I02811 Preparation 3, Sulfonyl Chloride of Intermediate 88 Fraction 3: LCMS
(Method F, ES-API; quenching into morpholine): RT 1.47 mm, m+morpholine-CI =261; 1H NMR (400 MHz, CDC13): 8 8.26 (1H, s), 4.95 (1H, sept., J = 6.7 Hz), 1.68 (6H, d, J = 6.7 Hz).
Intermediate 93. (112)-ntethyl 1 -(4-1113 orophenv1)-64(1-propv1-111-pvrazol-4-v1)sulfon 1)-4.4a,5.6,7,8-hexallvdro-11-1-vvrazolo13,4-glisottuinoline-4a-carboxylate 11,0 Nk/ NN
--..
102821 Made by the method of Intermediate 33, using HC1 (4M solution in dioxane) in place of trifluoroacetic acid/dichloromethane. LCMS (Method F, ES-API): RI 2.22 min, m+H = 500.
Intermediate 94.
Me0 0 0 ii..0 (R)-methyl 1-(4-fluoropheny1)-64(2- N
metliy1-2E1-1,2,3-trituol-4-N I N I
'N-- =
its N
Isomer A -yDsulfony1)-4õ4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinoline-4a- *
carboxylate Me0 0 R
(R)-methyl 1-(4-fluorophcny1)-641-methyl- I H-1,2,3-triazol-5- N N
yDsulfony1)-4,4a,5,6,7,8-hexahydro-Isomer B
1H-pyrazolo[3,4-g] isoquinoline-4a-carboxylate 1/4 Me0 000 (R)-methyl 1 -(4- fluoropheny1)-6-((1- ;Si N
"Nmethy1-1H-1,2,3-triazol-4- N
i I N Y

A ,sulfony1)-4,4a,5,6,7,8-hcxahydro-N N
Isomer C ' µ
1H-pyrazolo[3,4-g] isoquinoline-4a- , carboxylate \ i F
[02831 Made from Preparation 1 of Intermediate 89 by the method of Intermediate 33, using FICI (4M solution in dioxane) in place of trifluoroacetic acididichloromethane. LCMS (Method F, ES-API): RI 2.10 min, m-111 = 473.1.
Intermediate 95.
1 (R)-methyl 1-(4-Me0s.sei:.0 0 fluoropheny1)-6-02-propyl-214-1,2,3-triazo1-4-N' I
y 1)sulfony1)-4,4a,5,6,7,8- s N^-isomer hexahydro-1H-A

pyrazolo[3.4-g]isoquinoline-4a-carboxylate F
(R)-methyl 1-(4-0 r--\
fluorophenyl)-6-0 Me0-0 0 1-propyl- r- \\,e, I
1H-1,2,3-triazol-5-Nis, yp N ,-.) -- sulfony1)-4,4a,5,6,7,8- "\õ.. ....---.,, 1 ',' 4 isomer - N
hexahydro- 1H-B --pyrazolo[3,4-g]isoquinoline-4a- \ 1 carboxylate F
(R)-methyl 1-(4-Me0 000 fluoropheny0-6-((1-propy1-1H-1,2,3-triazol-4- N, yl)sulfony1)-4,4a,5,6,7,8- N ki i I s,11 Isomer sINI - 'N.."' ---- --- N
hexahydro- 1 H-C r--:c pyrazo io [3,4-g]isoquinoline-4a- --U
carboxylate 1.02841 Made from Preparation 1 of Intermediate 91 by the method of Intermediate 33, using Ha (4M solution in dioxane) in place of trifluoroacetic acid/dichloromethane.
LCMS (Method F, ES-API): RT 2.40 min, m+H = 501.2.
Example I. (R)-(1-(4-fluoroplieird)-6- (4-(irifilioroinethvI)Dhenyl)su1loaa11-4.4a,5.6.7,8-hexahvdro-1H-pvrazolo13.4-gli El i El i3-4a-v1)(nvrid in-2-vi)nieth anone N

NvI
N-0 io N I
µN F
FF
102851 A solution of (R)-(1-(4-fluorophcny1)-6-((4-(trifluoromethyl)phcnyl)sulfonyl)-4,4a.5.6,7,.8-hexahydro-IH-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)-(R/S)-methanol (3.1 g, 5.3 mmol) in dry dichloromethane (25 mL) was treated with 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxo1-3(1H)-one (3.2 g, 7.54 nunol; Dess-Martin periodinane) and the reaction mixture stirred for 1 hour at room temperature. The reaction mixture was cooled and treated with saturated sodium hydrogen carbonate solution (125 mL) followed by dichloromethane (50 mL).
The mixture was stirred for 10 minutes and the phases separated. The aqueous phase was extracted with further dichloromethane (x2) and the combined organic phases dried over sodium sulfate. The solids were removed by filtration, the filtrate was concentrated under reduced pressure and the residue purified by column chromatography on silica gel (gradient: 20-30%
ethyl acetate in cyclohexane) to afford (R)-(1-(4-fluoropheny1)-64(4-(trifluoromethyl)phenyl)sulfony1)-4,4a,5,6,7,8-hexahydro- I H-pyrazolo[3,4-g]isoquinoliii-4a-y1)(pyridin-2-yl)methanone as a pale yellow foam (2.20 g). The product was further purified by preparative Hplc (C-18 column eluting with 80% aqueous methanol) to give (R)-(1-(4-fluoropherly1)-6-04-(trifluoromethyl)phenyl) sultbny1)-4,4a,5,6,7,8-hexahydro-111-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-y1) methanone as a white solid (1.10 g). LCMS
(Method D, ES!):
RI 5.61 mm. m+H = 583.0; 1H NMR (400 MHz, CDCb): 6 8.62 (ddd, J = 4.8, 1.7, 1.0 Hz, 1 H); 7.85-7.86 (m, 1 H); 7.80-7.81 (m, 3 H); 7.70 (d, J = 8.3 Hz, 2 H); 7.44-7.45 (m, 3 H); 7.27 (s, 1 11); 7.16 (t, J = 8.5 Hz, 2 H); 6.49 (d, .1= 2.2 Hz, 1 H); 5.56 (dd, J =

12.3, 2.1 Hz, 1 H); 4.26 (d, .1= 16.9 Hz, 1 H); 3.86-3.89 (m, 1 H); 2.83-2.84 (m, 3 H); 2.54-2.56 (in, 2 H).
[0286] Alternative preparation of Example 1: (R)-tert-butyl 1-(4-fluorophenyI)-4a-picolinoyl-4a,5,7,8-tetraliydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate (109.5 g) was suspended .. with stirring in a 4 N HCl/dioxane solution (250 mL) at 20-25 C. After deprotection was complete (1.5 hours) the solution was concentrated to dryness to give 157.1 g of the corresponding HC1 salt as an amber oil. The salt was suspended in dichloromethane (1.5 L) and Hunig's base (150 g, 1150 nunol) was added. When the suspension had cleared a solution of 4-(trifluoromethypbenzenesu1fony1 chloride (67.0 g. 275 mmol) in dichloromethane (100 m1.) was added. The reaction mixture was allowed to stir overnight at 20-25 C, then was quenched with water (500 mL). The organic layer was washed with 15% aqueous sodium chloride solution (500 mi.) and then concentrated. The crude product was purified by column chromatography on silica gel (300 g), eluting with heptane/ethyl acetate (4:1 to 1:1), to give (R)-(1-(4-fluoropheny1)-644-(trifluoromethyl)phenypsulfony1)-4,4a,5,6,7,8-hexahydro-IH-pyrazol of 3,4-glisoq u inolin-4 a-.. yl)(pyridin-2-yl)methanone (78 g) as a pale yellow powder.
[0287] The following examples were similarly prepared from the appropriate intermediate:
Example I A. (R)-(1-(4-fluarophenv1)-644-(trifluoromethyl)phenvi)sulfonvi)-4,4a.5,617,8-hexahvdro-111-fn razolo13.4-1disoqu in oli n-4a-y1)(1-rnethyt-1 midazol-2-yl)methanone \ N 000 N
N I
I F
F =
()___ 102881 LCMS (method E), Rt = 12.56 min (MH)+ 586.2; NMR (400 MHz, CDCI3): 8 7.82 (d, J = 8.2 Hz, 2 H); 7.71 (d, J = 8.3 Hz, 2 F1); 7.42-7.43 (m, 2 H); 7.31 (s, 1 H); 7.14-7.15 (m, 3 El); 6.97 (s, 1 F1); 6.53 (d, J = 2.3 Hz, 1 H); 5.59 (dd, J = 12.5, 2.1 Hz, 1 H); 4.41 (d, J = 16.7 Hz, 1 H); 3.92-3.95 (m, 1 IT); 3.83 (s, 3 H); 2.81-2.82 (m, 3 H); 2.57-2.59 (m, 2 H).

Example 1B. (11)-(1-(4-fluorophenv1)-6-04-(trifluoromethvl)phenvOstilfonth-4.4a.5,6.7,8-hex an vd ro-111-pvrazolo13.4-glisoquinolin-4a-v1)(0vridin-3-y1)methanone r, o o µµ,1 lir 7 FF
[02891 LCMS (Method D, ES1): RI 5.17 min, m+H = 583.0; 1E1 NMR (400 MHz, CDC13): 8 8.91 (d, J = 2.2 Hz, 1 H); 8.71 (dd, J = 4.8, 1.7 Hz, 1 H); 8.01 (dt, J = 8.0, 2.0 Hz, 1 H); 7.94 (d, = 8.2 Hz, 2 H); 7.82 (d, J= 8.3 Hz, 21); 7.41-7.42 (m., 3 H); 7.35 (dd, J =
8.0, 4.8 Hz, 1 H); 7.18 (t, J = 8.5 Hz, 2 H); 6.44 (s, 1 H); 4.60 (dd, J = 11.4, 1.9 Hz, 1 H); 3.89 (dd, J = 10.9,4.9 Hz, 1 H); 3.38 (d, J = 17.5 Hz, 1 H); 2.80 (d, J = 17.6 Hz, 1 H); 2.55 (d, J = 11.4 Hz, 1 H); 2.48 (td, J =
11.5, 3.4 Hz, 1 H); 2.26-2.29 (m, 2 H).
Example IC. (R)-(1-(4-lluoroDhenv1)-644-(trifluorometlivhpherivOsullonv1)-4,4a.5,6,7.8-hexahvdro-111-pvrazolof3.4-2,1isoquinolin-4a-v0(thiazol-2-vhinethanone ri4 0 o o N1*
N
102901 LCMS (Method D, ESI): RI 5.50 min, m+H = 589.0; 1 H NMR (400 MHz, CDC13): 6 8.00 (d, .1= 3.1 Hz, 1 H); 7.83 (d, J = 8.2 Hz, 2 H); 7.68-7.69 (m, 3 H); 7.42-7.43 (m, 2 H); 7.29 (s, 1 H); 7.17 (t, J = 8.5 Hz, 2 H); 6.54 (d, J = 2.3 Hz, 1 I1); 5.51 (dd, J=
12.5, 2.1 Hz, 1 H); 4.20 (d, J = 16.8 Hz, 1 H); 3.91-3.95 (m, 1 IT); 2.85-2.86 (m, 3 H); 2.57-2.59 (m, 2 H).
102911 Alternative preparation of Example le: (R)-tert-butyl 1-(4-fluoropheny1)-4a-(thiazole-2-earbony1)-4a,5,7,8-tetrahydro-IH-pyrazolo[3,4-g]isoquinoline-6(4H)-earboxylate (76.1 g) was deprotected using 4 N HClidioxane solution (400 tnL) at 20-25 C. After reaction was complete (3 h) the solution was concentrated to dryness to provide 91.4 g of the corresponding HCI salt as an amber oil. The salt was suspended in dichloromethane (1.0 L) and Hunig's base (85.0 g , 650 mmol) was added. When the suspension became a clear solution 4-(trifluoromethypbenzenesulfonyl chloride (37.2 g, 152 rnmol) in dichloromethane (100 inL) was added. The mixture was stirred overnight at 20-25 C. The reaction mixture was quenched with water (250 mL) and the organic layer washed with 15% aqueous sodium, chloride solution (500 mL) then concentrated. The crude product was purified twice by column chromatography on silica gel (300 g then 800 g), eluting with heptanelethyl acetate (3:1), to give (R)-(1-(4-fluoropheny1)-6-04-(trifluoromethypphenyl)sulfonyl)-4,4a,5,6,7,8-h.exahydro-lH-pyrazolo[3,4-disoquinolin-4a-y1)(thiazol-2-yOmethanone (54.2 g) as a pale yellow powder.
Example ID. (11)-(1-(4-fluorophenv1)-644-0rifluoromethyDphenyllsulfonv1)-4,4a.5.6,7,8-hexahvdro-IH-pyratolo13.4-glisotiainolin-4a-v1)(5-methvi-1,3,4-oxadiazol-2-vDmethanone N N
_4.

µN, N1 1N (001 /
[0292] LaviS (Method D, ES1): RT 5.24 min, rnfil - 588.0; 111 NMR (400 MHz, CDC13): 6 7.82-7.84 (in, 4 H); 7.40-7.41 (m, 2 II); 7.33 (s, 1 H); 7.17 (t, J = 8.5 Hz, 2 H); 6.58 (d, J = 2.4 Hz, 1 H); 5.27 (dd, = 12.9,2.1 Hz, 1 H); 4.14 (d, J = 16.8 Hz, 1 H); 3.97 (t, J = 7.9 Hz, 1 H);
2.85-2.87 (m, 2 H); 2.75 (d, j = 12.9 Hz, 1 H); 2.65 (s, 3 H); 2.56-2.58 (m, 2 H).
Example 1E. (R)-(1-(4-11Thorophenv1)-644-(trifluoromethyl)phenvi)stillonyl-4.4a<5,6.7,8-IhAalivdro.-11.1-pa-razoloj3.4-21isocguinolin-4a-v1)(oxzol-.4-.1.1methalione "z"---N
(3\,,....--;)=-d 0 0 0 Si N I
\
/..õ..c j F
/ F F

F
[0293] LCMS (Method D, ESI): RT 5.32 min, m-i-H = 573.0; 1H NMR (400 MHz, CDC13): 8 7.86 (d, .1 = 8.2 Hz, 2 H); 7.76-7.78 (m, 3 H); 7.41 (dd, J = 8.6, 4.8 Hz, 2 H); 7.35 (s, 1 H); 7.31 (s, 1 H); 7.17 (t, J = 8.4 Hz, 2 H); 6.54 (s, 1 H); 5.38 (d, J = 12.6 Hz, I
H); 4.12 (d, J: 16.8 Hz, 1 H); 3.91-3.94 (in, I H); 2.82-2.84 (m, 3 H); 2.55-2.58 (m, 2 H).
Example 1F. (R)-(1-(4-fhwrophenv1)-6-44-(trilluoromethvflphenvI)sulfony1)-4,4a,5,6,7.8-hexahydro-11I-pyrazolo13.4-glisoaulnolin-4a-v1)(oxatol-2-vDmethanone (11 N 1110) F \NI i FF
.---r),/::-/
,,, \
F
[0294] LCMS (Method D, ESI): RI 5.35 min, m+H = 572.9; 1H NMR (400 MHz, CDC13): 8 7.86 (d, .1= 8.2 Hz, 2 H); 7.77-7.78 (m, 3 H); 7.40-7.41 (m, 2 H); 7.35 (d, .1= 0.7 Hz, 1 H); 7.30 (s, 1 H); 7.16 (t, J = 8.5 Hz, 2 H); 6.54 (d, J = 2.3 Hz, 1 H); 5.38 (dd, J =
12.6,2.1 Hz, 1 H);4.12 (d, J = 16.8 Hz, 1 H); 3.91-3.94 (m, 1 H); 2.82-2.83 (m, 3 H); 2.55-2.57 (m, 2 H).
Example 1G. (R)-(1-(4-fluoropheny1)-64(4-(trifluoromethvl)phenyl)sulfonyl)-4,4a..5,6,7,8-hexahydro-1H-pyrazolol3.4-glisoquinolia-4a-y1)(furan-2-v1)methanone 0 µN ii ..= S
/

µN F
F F
F
102951 LCMS (Method D, ESI): RT 5.38 min, m+H = 571.9; 1H NMR (400 MHz, CDC13): 6 7.86 (d, .1= 8.2 Hz, 2 H); 7.75 (d, 3 = 8.2 Hz, 2 H); 7.57 (dd, 3:- 1.7, 0.8 Hz, 1 4); 7.41-7.42 (m, 2 H); 7.31 (s, 1 H); 7.22 (dd, .1 = 3.6, 0.8 Hz, 1 H); 7.15-7.16 (m, 2 H);
6.51-6.52 (m, 2 F1); 4.96 (dd, J - 12.3, 2.0 Hz, 1 H); 3.86 (dd, J - 10.8, 5.6 Hz, 1 H); 3.63 (d, J=
16.9 Hz, 1 H); 2.76-2.78 (m, 3 H); 2.58-2.60 (m, I H); 2.47 (d, .1. = 14.8 Hz, 1 H).
Example 111. (R)-(1-(4-fluoronhenv1)-64(4-(trif1uoromethv1)ohenµ hs a I fonv1)-4.4a.5,6.7.8-Itexahvd ro- I 1-1-Dvrazolo13,4-21isoeuino1in-4a-v1)(thioDhen-2-yl)m ethanol) e \ 0 0 0 "s ..._ * F
F
F
102961 LCMS (Method D, ESI); RI 5.56 min, m+H = 587.9; 1H NMR (400 MHz, CDC13): 6 7.92 (d, J = 8.2 Hz, 2 H); 7.76-7.78 (m, 3 H); 7.61 (dd, J = 5.0, 1.1 Hz, 1 H); 7.45 (dd, J = 8.7, 4.7 Hz, 2H); 7.36(s, 1 H); 7.19 (t, J = 8.4 Hz, 2 H); 7.03 (dd, i= 5.0, 3.9 Hz, 1 H); 6.51 (s, 1 H);
4.64 (d, .1= 11.5 Hz, 1 H); 3.87 (d, J = 9.1 Hz, 1 H); 3.41 (d, .1= 17.5 Hz, 1 11); 2.82 (d, .1 = 17.5 Hz, 1 H); 2.67 (d, J = 11.5 Hz, 1 H); 2.56-2.60 (m., 1 H); 2.47-2.50 (m, 1 II); 2.39 (d, J = 13.6 Hz, 1 H).
Example 11. (H)-(1-(4-11uorophenv1)-6-(m-tolvIstalfonyl)-4.4a,5,6,7,8-ttexallvdro-111-pyrafolo,13.4-glisoquinolin-4a-v11(oxazol-2-v1)methanone ell ..µ,/,.
/
N, 1 N
IL....;,./...,., N
*
F
[02971 LCMS (Method F, ES-API): RT 2.53 min, m+H = 519.1; 1H NMR (400 MHz, CDC13): 8 7.82 (1H, d, J = 0.6 Hz), 7.55-7.52 (211, m), 7.44-7.38 (511, m), 7.31 (111, s), 7.19-7.13 (2H, m.), 6.52 (1H, d, J= 2.3 Hz), 5.40 (111, dd, J = 12.5, 2.0 Hz), 4.12 (1H, d, J = 16.9 Hz), 3.91-3.85 (111, m), 2.92-2.82 (211, m), 2.68 (1H, d, J = 12.5 Hz), 2.53-2.42 (511, m).
Example U. (R)-(144-fluorepltenv1)-6-(m-tolvlstilfonvi)-4,4a,5.6,7.8-hexahvdro-1.H-pvratolof3.4-21isoquiao/in-4a-Mpvrimidin-2-N-1)methamme r.:;,-;-.., L.'s,- 1 -a _ 0 0 N IX
N
N, I j ii , N---- ..--- `---.1,-,---ci F
102981 LCMS (Method F, ES-API): RT 2.38 min, m+H = 530.2; 1H .NMR (400 MHz, CDC13): 6 8.92 (2H, d, .1. = 4.8 Hz), 7.49-7.36 (7H, m), 7.32 (1H, s), 7-19-7.13 (2H, m), 6.47 (1H, d, J = 2.1 Hz), 5.12(111, dd, .1 = 12.1, 2.0 Hz), 4.13 (1H, d, J. = 16.9 Hz), 3.80-3.76 (1H, m), 2.95 (1H, d, .1= 16.9 HZ), 2.88-2.79 (1H, m), 2.61 (1H, d, .1 = 12.2 Hz), 2.46-2.37 (511, m).
Example 1K. (R)-(6-{(3,5-difluorophenyl)sulfonv10-1-(4-fluoronhenv1)-4,4a,5,6,7,8-Itexahydro-1/1-ovrazolo[3.4-uliso(Iulao1in-1a-vi)(4-ine1hoxypyri(Iin-2-v1)methagion e OMe ====ço 0õ0 N'µS/
N I =
[02991 I..CMS (Method F, ES-API): RT 2.78 min, m+II = 581.2; I H NMR (400 MHz, CDC13): 8 8.46 (111, d, J = 4.9 Hz), 7.45-7.39 (3H, m), 7.29 (111, s), 7.21-7.14 (4H, m), 7.00-6.95 (2H, rn.), 6.49 (111, s), 5.63-5.60(111, m), 4.30 (111, dd, J = 16.9, 2.1 Hz), 3.88-3.83 (411, m), 2.89-2.78 (311, m), 2.63-2.57(111, m), 2.53-2.49(111, m).
Example 1L. (R)-(4-ethylpyridin-2-0)(1-(4-flaioroplknr1)-6-({3,4.5-trifluorophenvi)sulfonv1)-4,4a,5,6,7,8-hexahvdro-1H-pvrazolo13õ4-0soq no1in-4a-v1)methunone 0 0õ0 N.;Si F
NI/ I
1\1 [03001 LEM'S (Method F, ES-A.P1): RI 3.19 min, = 597.2; 111 NMR (400 MHz, CDC13): 8 8.49 (1111, dd, J =4.9, 0.6 Hz), 7.70 (111, m), 7.45-7.41 (211, m), 7.33-7.30(411, m), 7.19-7.14(2H, m), 6.50 (1H, d, J = 2.0 Hz), 5.58 (1H, dd, J = 12.5, 2.0 Hz), 4.24(1H. d, .1= 16.9 Hz), 3.91-3.86 (1H, m), 2.92-2.80 (3H, m), 2.73-2.67(311, m), 2.56-2.51 (1H, m), 1.27 (3H, t, J
= 7.5 Hz).
Example !M. (R)-(1-(4-fluaropheny1)-6-((3,4,5-trilluorophen-v1)sullonv1)-4,4a.5,6,7.8-hexalivdro-111-nvrazolo13A-glisoquiliolin-4a-v1)(4-metlioxvnyridin-2-v1)metharione 011ie ri*
*N- o oµ gP
4 IIisi F
T
-- "
Njcs I . ]
N--"-",---.'" F
/
F
[03011 I..CMS (Method F, ES-API): RT 2.97 min, m+II = 599.2; III NMR (400 MHz, CDC13): 8 8.42 (1H, d, J = 4.9 Hz), 7.45-7.41 (21-i, m), 7.37 (111, d, J = 2.5 Hz), 7.33-7.30 (2H, m), 7.27 (1H, s), 7.19-7.14 (2H, m), 6.97(111, dd, J = 5.8, 2.5 Hz), 6.50(111, d, J = 2.0 Hz), 5.58 (111, dd, J = 12.1, 2.0 Hz), 4.28 (iii, d, J = 16.9 Hz), 3.91-3.85 (411, m), 2.91-2.78 (311, m), 2.70-2.63 (11-1, ro.), 2.55-2.50 (Hi, m).
Example 2. (R)-(1-(4-fluoropheny1)-64(4-fluoroulienvI)sulfonsin-4.-laõ5,6,7,8-hexalivdro-ln-pvrazolof3,4-111asoquinolin-43-v11(pvritlin-2-01)med Lin none ...' N
i "--.. (-) 0 o µµ,/
Ng I ''''N"'S"'=('-`1 µIsl *
F
[03021 A solution of (R)-(1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-IH-pyrazol.o[3 A-disoquinolin4a-y1)(pyridin-2-y1.)methanon.c in dichloromethane (2.5m1) (2.7 miõ ¨0.2 =not) containing disiopropylethylamine (174p1, imm.ol) was added to 4-fluoro-phenyl sulfonyl chloride (48 mg, 0.25 mmol) and diisopropylethylamine (100 ut, 0.57 mmol) and the mixture stirred for 1.25 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (gradient: 20-30%
ethyl acetate in cyclohexane) to afford (R)-(1-(4-fluoropheny1)-64(4-fluorophenyl)sulfony1)-4,4a,5,6,7,8-hexahydro-11-1-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-yl)methanone as a white solid (72 mg). LCMS (Method D, ESI): RT 5.32 min, m-4-1I. = 533.0; HI NMR (400 MHz, CDCI3): i5 8.62.-8.63 (m, 1 H); 7.85-7.86 (m, 2 H); 7.69-7.70 (m, 2 H); 7.44-7.45 (m, 3 H);
7.28 (s, 1 H); 7.14 (dt, .I. = 12.9, 8.5 Hz, 4 H); 6.48 (d, J = 2.2 Hz, 1 H); 5.51 (dd, J = 12.2, 2.1 Hz, 1 14); 4.29 (d, J =
16.9 Hz, 1 H); 3.82-3.86 (in, 1 H); 2.84-2.86 (m, 2 H); 2.72 (d, J = 12.2 Hz, 1 H); 2.46-2.51 (m, 2H).
[0303] The following examples were similarly prepared from the appropriate intermediate:
Example 2A. (R)-(64(3-fltiorobenzyl)sulfonv1)-1-(4-fluorophenvb-4.4a,5,6.7,8-hexahydro-IH-pyrazolo13,4-21isoQuinolin-4a-vO(tliiazol-2-%11)methanone r \s a 0 9 n F
N i 0 'N--,--c_r) 4Ik F
[0304] LCMS (Method F, ES-API): RT 2.48 min, m+H = 552.9; 1H NMR (400 MHz, CDC13):
5 8.07 (1H, d, J = 3.1 Hz), 7.68 (1H, d, J = 3.1 Hz), 7.47-7.41 (2H, m), 7.35-7.30 (2H, m), 7.20-7.14 (2H, m), 7.09-7.04 (3H, m), 6.53 (1H, s), 5.43 (1H, dd, J = 7.1, 2.0 Hz), 4.23 (1H, d, .1=
16.8 HA 4.08 (1H, d, J.= 13.8 Hz), 4.02 (1H, d, J = 13.8 Hz), 3.61-3.59 (1H, m), 3.07 (1H, d, J
= 13.1 Hz), 2.85 (1H, d, J = 16.8 Hz), 2.73-2.64 (2H, m), 2.45-2.37 (1H, m).
Eva mple 2B. ((4aR)-1-(4-l1uorophenv1)-6-(WRIS)-te1rahvdrofuran-2-0methyl)stilfonv1)-5 4,411.5,6,7.8-hex alt vtl re- I H-pyrazolol3,4-glisoquinolin-4a-v1)(thiazoi-2-vOrnethanotie .7---N

s =c-------"*'. N - i I

sN--''' ="-CJ) )----F
[0305] LCMS (Method F, ES-API): RT 2.28 mm, m-1-H = 528.9; 1H NMR (400 MHz, CDC13):
5 8.07-8.06 (1H, m), 7.66 (1H, d, J = 2.9 Hz), 7.48-7.44(2H, in), 7.33 (1H, s), 7.20-7.14(2H, m), 6.57 (1H, s), 5.47 (1H, ddd, J ¨ 17.5, 13.1, 2.2 Hz), 4.32-4.10 (2H, m), 3.88-3.72 (3H, m), 3.25 (1H, dd, I = 43.6, 13.4 Hz), 3.13-2.81 (5H, m), 2.56-2.50 (1H, m), 2.40 (1H, s), 2.13-2.02 (1H, m), 1.91-1.84 (2H, m).
Example 2C. (R)-(1-(4-fluorophenvI)-6-(o-tolvIsulfonv1)-4,4a.5,6,7,8-hexahydro-pyrazolo13,4-z liSOCIainolin-4a-11)(1)vridin-2-µ1)niet Ilan one !I
\ pS/
`'=
I
[03061 LCMS (Method F, ES-API): RT 2.61 min, m+H = 528.8; 1H NMR (400 MHz, CDC13): 6 8.34 (1H, ddd, J = 4.7, 1.8, 0.8 Hz), 7.85 (1H, dd, J = 7.6, 1.5 Hz), 7.81-7.79 (1H, m), 7.65 (1H, dt, J = 7.6, 1.8 Hz), 7.46-7.41 (2H, m), 7.32 (1H, ddd, J = 7.6, 4.8, 1.4 Hz), 7.24-7.14 (5H, m), 6.93-6.91 (1H, m),6.52 (1H, s), 5.49 (1H, dd, J= 12.8, 2.1 Hz), 4.20 (1H, d, J = 16.9 Hz), 3.98-3.95 (1H, m), 3.08 (1H, d, J = 12.8 Hz), 2.90-2.82 (3H, m), 2.60-2.54 (1H, m), 2.34 (3H, s).
Example 21). (R)-(64(4-etlivlonenvbsulfonv1)-1.-(4-fluoropheny1)-4,43,5,6,7,8-hexahydro-1 H-DV razoloI3,4-g isoqu n oli n-4 a-v1)(pyri din-2-vDmeth a non e I
,,-- 0 0 0 N
N
103071 LC,MS (Method F, ES-API): RI 2.75 min, m+H = 542.8; 1H NMR (400 MHz, CDC13): 6 8.66 (1H, ddd, J = 4.7, 1.7, 0.8 Hi), 7.91-7.89(111, m), 7.84(111, dt, J = 7.5, 1.8 Hz), 7.61-7.58 (2H, m), 7.47 (1H, ddd, J = 7.5,4.7, 1.4 Hz), 7.44-7.40(2H. m), 7.27-7.22(3H, m), 7.19-7.13 (2H, m), 6.46 (1H, d, J = 2.1 Hz), 5.50 (1H, dd, J = 12.4, 2.1 Hz), 4.31 (1H, d, .1= 16.9 Hz), 3.84-3.79 (1H, m), 2.91-2.77 (2H, m), 2.72-2.65 (3H, m), 2.47-2.38 (2H, m), 1.25 (31-1, t, J
= 7.5 Hz).
Example 2E. (R)-(1-(4-fluoropheny1)-6-(m-tolµ istilfonv1)-4,4a,5,6,7,8-hexalrydro-1H-pyrazolo13,4-alisoaninolin-4n-In(nvridin-2-N hanethalione = õ../1 0 0 N, I N 110 S._ [03081 LCMS (Method F, ES-API): RT 2.62 min, m+H = 528.8; 1H NMR (400 MHz, CDC13): 8 8.66 (111. ddd, J = 4.7, 1.7, 0.8 Hz), 7.91-7.89 (1H, m), 7.84 (1H, dt, J = 7.4, 1.7 Hz), 7.50-7.40 (511, in), 7.36-7.34 (2H, m), 7.29 (1H, s), 7.19-7.13 (2H, m). 6.47 (1H, d, J = 2.1 Hz), 5.51 (1H, dd, J = 12.4, 2.1 Hz), 4.31 (11i, d, .1= 16.9 Hz), 3.84-3.80 (IH, m), 2.92-2.78 (211, m), 2.68 (IH, d, J= 12.4 Hz), 2.49-2.40 (511, m).
Example 2E fft)-(643-chlorophenvl)sulfopil)-1-(4-fluorpphenil)-4,4a,5_,0_,18-hexahydro-I H-pyrazolo13,41-gl isoq uino n -4 a-v1)(pyridin-2-yl)metha none ,C) 0 0 \\s/1 =

Ns I \i [03091 LCMS (Method F, ES-API): RT 2.68 min, mill = 548.8; 111 NMR (400 MHz, CDC13): 8 8.66 (IH. ddd, J = 4.7, 1.7, 0.8 Hz), 7.91-7.88 (1H, m), 7.84 (111, di. J = 7.5, 1.8 Hz), 7.66-7.65 (1112m), 7.59-7.56 (11I, m), 7.52-7.47 (2H, m), 7.46-7.41 (311, m), 7.29 (111, s), 7.19-7.13 (2H, m), 6.49 (1H, d, = 2.1 Hz), 5.55 (1H, dd, J =12.2, 2.1 Hz), 4.29 (1H, d, J = 16.9 Hz), 3.87-3.82 (1H, m), 2.92-2.75 (3H, m), 2.56-2.47 (2H, m).

Example 26. (R)-i I 44-fluoroplienv1)-6-((3-nietboxvphenvi)sullon-v1)-4,4a,5,6:7.8-hexahvilro-111-pyrazolol3A-g1isoquinolin-4a-v1)lpµ ridin-2---0)methanone I s- 0 0 /0 µµS' [03101 I,CMS (Method F, ES-API): RT 2.60 min, m+H = 545.2; 1H NMR (400 MHz, .. CDC13): 8 8.65 (iii, ddd, J = 4.7, 1.7, 0.8 Hz), 7.91-7.88 (111, m), 7.83 (l ii, dt, J = 7.5, 1.8 Hz), 7.49-7.36 (4H, m), 7.29 (211, m.), 7.19-7.13 (311, m), 7.05 (lii, dd.d, J =
8.3, 2.5, 0.9 Hz), 6.47 (Iii, d, J = 2.1 Hz), 5.50(111, dd, J = 12.2,2.! Liz), 4.30 (lii, d, J = 16.9 Liz), 3.85-3.80 (411, m), 2.91-2.78 (2H, m), 2.72 (111, d, J= 12.2 Hz), 2.51-2.44(211, m).
Example 211. (R)-(64(4-chlore-3-fluorophenvOsulfonv1)-1-(4-fluoropheav1)-4,,la,5.617,8-hexahvdro-1H-pyrazolor3A-glisoquinolia-4a-v1)(pyridin-2-v1)methattone N

F
N I N
sN
[0311.1 LCMS (Method F, ES-API): RT 2.78 min, m+El = 567.1; 111 NMR (400 MHz, CDCI3): 8 8.63-8.61 (111, rn), 7.89-7.82(211, m), 7.50-7.41 (611, m), 7.28 (1H, s), 7.19-7.13 (2H, m), 6.50 (1H, d, J = 2.1 Hz), 5.54 (1H, dd, J = 12.2, 2.1 Hz), 4.27 (111, d, S
= 16.9 Hz), 3.89-3.85 .. (1.H, m), 2.90-2.79 (3H, in), 2.61-2.49 (2H, lay Example 21. (R)-(1-(4-fluoronhenv11-64(4-methowpbenvI)sulfonvi)-4,4a,5,6,7,8-hexalivdro-IH-pvrazolo13.4-21isaaninolin-4a-v1)(Dvridin-2-v1)1/ let ha none N

N I N
mgrrr OMe [0312] LCMS (Method F, ES-API): RT 2.57 min, m+H = 545.2; 1H NMR (400 MHz, CDC13): 8 8.63 (1H, ddd, J = 4.7, 1.7, 0.8 Hz), 7.91-7.88 (1H, m), 7.83 (1H, dt, J = 7.6, 1.8 Hz), 7.64-7.60 (2H, m), 7.48-7.40 (3H, m), 7.29 (1171, s), 7.19-7.13 (211, m). 6.93-6.89 (211, m), 6.47 (111, d, J = 2.1 Hz), 5.48 (11I, dd, J = 12.2,2.1 Liz), 4.30 (1H, d, J = 16.9 Hz), 3.85-3.79 (4171, m), 2.90-2.77 (2H, m), 2.65 (111, d, I = 12.2 Hz), 2.48-2.39 (21I, m).
Example 2.1. (R)-(64(3-11uoro-4-methylphenvi)sulfonvi)-1-14-fluorophenvi)-4,42,5,6.7.8-hexahydro-111-iivrazoloPA-glisoginimlin-4a-v11(tivridin-2-y1)Inetbaitorie LL .o 0,p F
N

N
[0313] LCMS (Method F, ES-API): RI 2.74 min, m+El = 547.2; 1H NMR (400 MHz, CDC13): 8 8.65 (1H, ddd, J = 4.7, 1.7, 0.8 Hz), 7.91-7.88 (1H, m), 7.84 (1H, dt, J = 7.6, 1.8 Hz), 7.49-7.40 (3H, m), 7.37 (1H, dd, J = 8.1, 2.1 Hz), 7.33-7.26 (3H, m), 7.19-7.13 (2H, m), 6.48 (1H, d, I = 2.1 Hz), 5.52 (1H, dd, J = 12.2,2.1 Hz), 4.30(1H, d, J = 16.9 Hz), 3.85-3.80 (1H, m), 2.91-2.77 (2H, m), 2.71 (1H, d, J = 12.2 Hz), 2.51-2.44 (2H, m), 2.31 (3H, d, J = 1.7 Hi).
Example 2K. (R)-(1-(4-fluorophenx.1)-6-(phelivlsulfonv1)-4,42,5,6,7,8-hexahvdro-lH-pyrazolo13,4-211sooninolia-4a-v1)( Iry ridin-2-x.1)methanone N
! õ..a1c) 00 "-by---[03141 LCMS (Method F, ES-API): RT 2.57 min, m+H = 515.2; 1H NMR (400 MHz, CDC13): 8 8.66 (1H, ddd, J = 4.7, 1.7, 0.8 Hz), 7.92-7.89 (1H, m), 7.84 (1H, dt, J = 7.6, 1.8 Hz), 7.71-7.68 (2H, m), 7.58-7.53 (1H, m), 7.50-7.40 (5H, m), 7.29(111, s). 7.19-7.13 (2H, m), 6.47 (111, d, J = 2.1 Hz), 5.53 (1H, dd, J = 12.2,2.1 Hz), 4.31 (1H, d, J = 16.9 Hz), 3.85-3.81 (1H, m), 2.91-2.78 (2E1, m), 2.67 (111, d, I = 12.2 Hz), 2.48-2.40(211, m).
EN ample 21.. (11)-(1-(441norophenv1)-64(2-flooroph vl)stv s. 11-1.4a,5,6,7,8-hexahvdro-III-nvratoloi3..4-giisoqui nob it-4a-v1Aps ridin-2-0)methanone I
p F
Sjj [03151 LCMS (Method F, ES-API): RI 2.57 min, m+H = 533.2; 1H NMR (400 MHz, CDC13): 68.64 (1H, ddd, 1 = 4.7, 1.7, 0.8 Hz), 7.85-7.82 (1H, m), 7.80 (1H, dt, J = 7.6, 1.8 Hz), 7.73-7.68 (1H, m), 7.52-7.41 (4H, m), 7.28 (1H, s), 7.19-7.10 (4H, m), 6.50 (1H, d, J = 2.1 Hz), 5.60 (1H, dd, I = 12.2, 2.1 Hi), 4.29 (1H, d, I = 16.9 Hi), 3.97-3.93 (1H, m), 3.01 (1H, dd, J =
12.8. 1.2 H42.91-2.72 (3H, m), 2.52-2.48 (111, m).
Example 2M. ( R ).- (1-(4-fluoropheav1)-6-((i-methyl-111-pyrazol-4-11)sulfony1)-4.4a,5,6,7,8-hexa hydro- ill-nvrazolo13.4-allsoquinohn-4a-v1)(PITidin-2-171)metlianone N
Lo 0µ /0 C,N
N N
[03161 LCMS (Method F, ES-API): RT 2.17 min, m+H = 519.1; 1H NMR (400 MHz, CDC-13): 8 8.66 (1H, ddd, J = 4.7, 1.7, 0.8 Hz), 7.91-7.89 (1H, m), 7.84 (1H, dt, J = 7.6, 1.8 Hz), 7.68-7.65 (2H, m), 7.49-7.42 (3H, m), 7.30(111, s), 7.20-7.14 (2H, m). 6.49 (111, d, J = 2.1 Hz), 5.46 (1H, dd, J = 12.2, 2.1 Hz), 4.31 d, J = 16.9 Hz), 3.91 (3H, s), 3.80-3.76 (1H, m), 2.91 (111:, d, = 16.9 Hz), 2.88-2.79 (1H, m), 2.68 (1H, d, -- 12.2 Hz), 2.50-2.41 (2H, m).
ENample 2N. (R)-( 1 -(4-fluerophettfl)-646-(trifluorornethybpyrid in-1-1.1)sulfonvi)-4,4a,57,8-hexahydro- I I 1-pvrazolo13,4-2 isoqui nolin-4a-v1)(nvridin-2-µ1)inethattone ILa,o 0 0 N ' N
=C,F3 103171 LCMS (Method F, ES-API): RI 2.65 min, m-1-H = 584.1; 1H NMR (400 MHz, CDC13): 8 8.97 (1H, d, J = 2.2 Hz), 8.63-8.61 (1H, m), 8.14 (1H, dd, J = 8.3, 2.2 Hz), 7.85-7.82 (2H, m), 7.73 (111, d, J = 8.3 Hz), 7.51-7.46 (1H, in). 7.44-7.40 (2H, m), 7.27 (1H, s), 7.20-7.14 (21-1, m), 6.50(1H. d, J = 2.1 Hz), 5.62 (1H, dd, J = 12.2,2.1 Hz), 4.22 (1H, d, J = 16.9 Hz), 3.96-3.92 (1H, m), 2.93 (1H, d, J = 12.6 Hz), 2.90-2.80 (2H, m), 2.73-2.66 (1H, m), 2.56-2.53 (1H, m).
Example 20. (R)-(1-(4-f1uoropheny1)-6-tosv1-4,4a,5,6,7,8-hex a hydro.- I H-p%
razolof 3,4-glisoquin olin-4a-371)(Dvridin-2-v1)methanone N
N I
\
[03181 LCMS (Method F, ES-API): RT 2.68 min, m+H = 529.2; 1H NMR (400 MHz, CDC13): 8 8.65 (1H, ddd, J = 4.7, 1.7, 0.8 Hz), 7.91-7.88 (1H, m), 7.83 (1H, dt, J = 7.6, 1.8 Hz), 7.58-7.56 (2H, m), 7.49-7.40 (3H, m), 7.29(111, s), 7.26-7.24 (2H, m). 7.19-7.13 (2H, m), 6.46 (111, d, J = 2.1 Hz), 5.49(111, dd, J = 12.2,2.1 Hz), 4.31 (1H, d, J = 16.9 Hz), 3.84-3.79 (1H, m), 2.90-2.77 (2H, m), 2.65 (111, dd, I = 12.8. 1.2 Hz), 2.47-2.38 (511, m).
ENamnle 2P. (R)-(64(4-fluoro-3-(trilluoromethyl)nbenvOsulfony1)-1-(4-fluorophenv11-4,4a,5,6,7,8-hexahvdro-111-DvrazoloT3,4-_gliso9ui no1ili-4a-y1)(rreridin-2-thmethanone I
0 0õ0 ,.CF3 st=I
[03191 . LCMS (Method F, ES-API): RI 2.78 min, m+H = 601.1; 1H NMR (400 MHz, CDC13): 8 8.62-8.60 (1H, m), 7.94 (1H, dd, J = 6.6, 2.2 Hz), 7.90-7.80 (3H, m), 7.49-7.39 (1H, m), 7.44-7.40(2H, m), 7.27 (1H, s), 7.26-7.22 (1H, m), 7.20-7.13 (2H, m), 6.50 (1H, d, J = 2.1 Hz), 5.55 (1H, dd, J = 12.2,2.1 Hz), 4.24 (1H, d, J = 16.9 Hi), 3.91-3.87 (1H, m), 2.90-2.80 (3H, m), 2.65-2.59 (1H, m), 2.55-2.50 (1H, m).
Example 20. (R)-44(1-(4-fluarophenv1)-4a-picalinav1-4a,5,7,8-tetrahydro-ln-mrazolo13,4-giisoouinolin-6(4H)-v1)sulfonvbbenzonitrile CIL,0 0, ash CN
, /2" = Ns [03201 LCMS (Method F, ES-API): RT 2.49 min, m+H = 540.0; 1H NMR (400 MHz, CDC13): 8 8.63 - 8.61 (11-1, in), 7.87 - 7.83 (2H, m), 7.82 - 7.77 (2H, m), 7.73 - 7.70(2H, m), 7.49 (1H, ddd, J = 6.2, 4.8, 2.7 Hz), 7.44 -7.39 (211, m), 7.27 (1H, m), 7.18 -7.12 (211, m), 6.49 .. (III, d, J = 2.0 Hz), 5.56 (1H, dd, J = 12.3, 2.0 Hz), 4.24 (1H, d, J =
16.9 Hz), 3.89 - 3.85 (11-1, in), 2.88 - 2.79 (3H, m), 2.61 - 2.49 (2H, m).
ENample 2R. (R)-(1-(4-fluorophenv1)-64(6-metholanyridin-3-vbsulfonv1)-4,4a.5,6,7,8-hexahydro-111-pyrazolo[3,4-glisoquino1in-4a-v1)(pyridin-2-vDmethanone '-===
I /N 0, pa N

r-0 \
[03211 LCMS (Method F, ES-API): RT 2.52 min, m+El = 546.0; 1H NMR (400 MHz, CDCI3): 8 8.61 (iH, ddd, J = 4.7, 1.7, 0.9 Hz), 8.49 (1H, dd, .1= 2.5, 0.6 HZ), 7.89 - 7.79 (2H, in), 7.76 (111, dd, J = 8.8, 2.5 Hz), 7.47- 7.41 (311, m), 7.28 (1H, s), 7.18 -7.13(211, m), 6.71 (1H, dd, J = 8.8, 0.6 Hz), 6.49(1K, d, I = 2.1 Hz), 5.52 (1H, dd, j - 12.2, 2.1 Hz), 4.27 (1H, d, J
= 16.9 Hz), 3.98 (3H, s), 3.90- 3.82 (1H, in), 2.90 - 2.75 (3H, m), 2.58 -2.48 (211, m).
Example 2S. (R)-(1-(4-fluorophenv1)-6-((tetruhydro-211-pvran-4-v0sulfonv1)-4,4a.5,6.7.8-hexalivdro-11.1-01 r3to1(313.4-glisoo Elia lin-4a-vi)(nvridi 3-2-0)methanone I

N
N
-.1 i--, ,r,--, \S1,1 /7---.-'' ----"N-1.,...,..6 I
'N' ---.-\ tif F
[0322] LCMS (Method F, ES-API): RT 2.21 min, m+H = 523.2; 1H NMR (400 MHz, CDC13): 8 8.69-8.68 (1H, m), 7.90-7.88(11-I, m), 7.84 (III, dt, J = 7.4, 1.8 Hz), 7.52-7.42(311, in), 7.29 (1H, s), 7.21-7.15 (2H, m), 6.52 OH, d, J = 2.1 Hz), 5.60 (IH, dd, J
= 12.2,2.1 Hz), 4.20 (1H, d, J = 16.9 Hz), 4.00-3.83 (4H, m), 3.28 (1H, d, J = 12.9 Hz), 3.15 (1H, di, J = 11.9, 2.5 1-14, 3.05-2.98 (211, m), 2.91 (111, d, J= 16.9114, 2.84-2.74 (1H, m), 2.55-2.51 (III, m), 1.84-1.65 (4II, m).
Example 2T. (R)-(6-(evelohexvisulfonvb-1.44-11uorophenv1)-4,4aõ.5,6,7,8-liexalts di-0-1111-1)vrazo1013,4-glisoouino1in-4a-v1)(nvridin-2-v1)methanone r'-`-'1=1 il 1 N' 1 7 o 'N----,---------õ,---=
c.I
F
103231 LCMS (Method F, ES-API): RT 2.65 min, m-I-H = 521.1; 1H NMR (400 MHz, CDC13): 8 8.68 (1H, ddd, J = 4.7, 1.7,0.9 HZ), 7.90 (1H, dt, J = 7.8, 1.2 Hz), 7.84 (IH, td, J =
7.5, 1.8 Hz), 7.30-7.43 (3H, m), 7.29 (111, s), 7.21-7.15 (2H, m), 6.53 (111, d, 1 = 2.1 Hz), 5.59 (1H, dd, J = 13.1, 1.9 Hz), 4.26 (1H, d, J = 16.9 Hz), 3.86-3.80 (1H, m), 3.26 (1H, d, J = 13.2 Hz), 2.98 (1H, td, J = 12.4, 3.2 HZ), 2.92 (1H, d J = 16.9 Hz), 2.78 (IH, tdd, J = 14.8, 5.8, 2.1 Hz), 2.64 (1H, tt, .1 = 12.3, 13 Hz), 2.51 (1H, dt, 1 = 14.7, 2.3 Hz), 2.02-1.95 (1H, m), 1.84-0.85 (9H, m).

Example 21J. (R)-(64(1-ethyl-IH-pyrazol-5-v1)sulfonv1)-144-11uorophenv1)-4.4a,5,6,7,8-liexahvdro-III-pyrazolo13.4-glisoquinolin-4a-y1)(4-(trifluoroinethIl)pyridin-2-yl)methanone , =-=.N 0 0õ0 N=,\;) N/
[0324j LCMS (Method F, ES-API): RT 2.67 min, m-F11 = 601.2; 1H NMR (400 MHz, CDC13): 6 8.81 (111, d, J = 4.9 Liz), 8.13 (1H, m), 7.71-7.69 (IF!, m), 7.47-7.42 (211, m), 7.40 (Iii, d, J = 2.0 Hz), 7.28 (1H, s), 7.21-7.15 (211, m), 6.59 (1H, d, J = 2.0 Hz), 6.55 (111, d, J = 1.6 Hz), 5.52 (111, dd, J ¨ 12.6,2.0 Hz), 4.35-4.23 (2H, Iti0.4.18 (1H, d, J ¨
16.9 Hz.), 3.92-3.87 (1H, m), 3.02 (IF!, d, J = 12.8 Hz), 2.92 (IF!, d, J = 16.9 Hz), 2.89-2.74(211, m), 2.59-2.55 (1H, m), 1.40 (311, t, J = 7.3 Hz).
Example 2V. (R)-(6-1(..4.5-dimetliv1-1H-pyrazol-4-0)sultonvi)-1-(4-filiorophenv!)-4Aai5,6,7,8-hexahydro-11:1-pvrazolo13,4-gliSOQUinolin4a-y1)(4-(trilluoroinethyl)pyridin-2-0)methanone -=-=
0 ovx4 N N
I PI
N
103251 LCMS (Method F, ES-API): RT 2.37 min, m+H = 601.3; 1H NMR (400 MHz, CDC13): 8 8.79 (1H, d, J = 4.9 Hz), 8.12 (1H, m), 7.67 (111, dd, J = 4.9, 1.0 Hz), 7.47-7.42 (2H, m), 7.27 (1H, s), 7.21-7.15 (2H, m), 6.53 (1H, d, .1= 2.1 Hz), 5.42 (1H, dd. J
= 12.3, 2.0 Hz), 4.19 (1H, d, .1= 16.9 Hi), 3.87-3.83(111, in), 2.93 (1H, d, J = 16.9 Hz), 2.91 (111, d, J = 12.8 Hz), 2.85-2.80 (1H, m), 2.72-2.76 (1H, m), 2.56-2.52 (111, m), 2.32 (6H,$).
Example 2W. (R)-(64(1H-imidazol-4-vbsulfonv1)-1-(4-fluorophenv1)-4,4a.5,6,7,8-itexahvdro-111-pyrazolof3A-disociuinolin-4a-8-1)(4-(trifluorometla%
yl)metimiloate 1 0 0õ0 ;Si N
NI I \>
[03261 I,CMS (Method F, ES-API): RT 2.18 min, m+H = 573.2; 1.H. NMR (400 MHz, CDC13): 6 10.27 (1H, br s), 8.84 (1H, d, J = 4.9 Hz), 8.13 (1H, m), 7.67 (1H, dd, J=4.9, 1.0 Hz), 7.64 (111, s), 7.49 (IH, s), 7.46-7.41 (2H, in), 7.30 (1H, s), 7.20-7.14(211, m), 6.51 (1H, d, J =
2.0 Hz), 5.55 (1H, dd, J = 12.6, 2.0 Hz), 4.22(111, d, J = 16.9 Hz), 3.88-3.84 (1H, m), 3.01 (1H, d, J = 12.7 Hz), 2.94 (LH, d, J = 1(.9 Hz), 2.86-2.7/ (IN, m), 2.71-2.64 m), (iH., in).
Example 3. (R)4144-iluoroph e v 1 )-64(6-morpliolinopvtidin-3-v1)sulfonv1)-4,49,54,7,8-h.exahvdral 11-pyrInA91:11-:gii s og tlitiOfin-4a-vn(pyridin-2-vi)inetlianone N

I N r [03271 A solution of (R)-(6-((6-chloropyridin-3-yl)sulfony1)-1.-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-yOmethanone (80 mg, 0.14 rnmol) and morpholine (150 j.tL, 1.73 mmol) in acetonitrile (2.5 mIL) was heated at 100 C for 70 minutes in a microwave reactor. The reaction mixture was concentrated and the residue purified by column chromatography on silica gel (gradient: 30-60% ethyl acetate in cyclohexane) to afford (R)-(1-(4-fluoropheny1)-6-((6-morpholinopyridin-3-yl)sulfony1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-g]isoquinolin-4a-y1)(pyridin-2-yOmethanone as a colourless glass (70 mg).
LCMS (Method D, ES!): RT 4.94 min, mi-H = 601.0; 1H NMR (400 MHz, CDC13): ö
8.63 (ddd, J = 4.8, 1.7, 0.9 Hz, 1 II); 8.44 (d, J = 2.5 Hz, 1 H); 7.84-7.85 (m, 2 H);
7.66 (dd, J = 9.1, 2.5 Hz, 11); 7.44-7.45 (m, 3 H); 7.29 (s, 1 H); 7.16 (t, J = 8.5 Hz, 2 H); 6.49-6.50 (m, 2 H); 5.49 (dd, J
= 12.1,2.1 Hz, 1 F1); 4.28 (d, = 16.9 Hz, 1 H); 3.80 (t, J = 4.8 Hz, 5 H);
3.63 (t, J = 4.8 Hz, 4 H); 2.83-2.85 (m, 2 H): 2.71 (d, i = 12.1 Hz, 1 H); 2.47-2.50 (m, 2 H).
Example 4. (R)-(1-(4-fluorophenv1)-646-(pwrolidin-1.-vbpvridin-3-vbsulfonvD-4,4a,5,6.7.8-hexahvdro-1H-pvrazolo13.4-gliSOquinolin-4a-v1)(thiazol-2-v1)methanone s, 0 9 1 or N
N
[0328j A mixture of (R)-(6-06-chloropyridin-3-yl)sulfony1)-144-fluorophenyl)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-g]isoquinolin-4a-y1)(thiazol-2-y1)methanone (100 mg, 0.180 mmol) and pyrrolidine (37.5 uL, 0.450 mmol) in acetonitrile (2 na.) was stirred at 40 C for 0.5hour.
The reaction mixture was cooled to room temperature and concentrated in vacuo to give a yellow oil. The crude product was purified by column chromatography on silica gel (gradient: 0-100%
ethyl acetate in isohexane) to give a white solid. This was further purified by preparative EIPLC
(Gilson, Acidic (0.1% Formic acid), Agilent Prep C-18, 5 gm, 21.2x50 mm column, 30-95%
acetonitrile in water) to afford (R)-(1-(4-fluoropheny1)-6-06-(pyrrolidin-l-y1)pyridin-3-y1)sulfony1)-4,4a,5,6,7,8-hcxahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(thiazol-2-yOmethanone as a white solid (51 mg). LCMS (Method F. ES-API): RT 2.43 min, m-E.H = 590.9;
1H NMR (400 MHz, CDC13): 8 8.45 (1H, dd, J = 2.0,0.5 HZ), 8.01 (1K, d, J= 3.1 Hz), 7.63-7.59 (2H, m), 7.4.6-7.41 (2H, m),7.29 (1H, s), 7.19-7.13 (2H; m), 6.51 (1H, d, J =
2.1 Hz), 6.27 (1H, d, J = 9.1 Hz), 5.47 (1H, dd,J = 12.2,2.1 Hz), 4.20 (1H, d, 5 = 16.8 Hz), 3.87-3.83 (1H, m), 2.91-2.82 (2H, m), 2.71 (1H, d, J = 12.3 Hz), 2.53-2.46 (2H, m), 2.06-2.04(4K, in), 1.33-1.24 (2H, m), 1.17-1.07 (2H, m).
Example 5. (R)-(1-(4-11uorophenv1)-644-fluorophenvi)sulfonv1)-4.42,5,6,7,8-hexahvdro-1H-nvraLolo13,4-12jisoilttiaolin-4a- % I gillittioi-2-v1)Inethanone es" 0 0, 0 N
N I
sN
[03291 A solution of (R)-tert-butyl 1-(4-fluorophenyl)-48-(thiazole-2-carbony1)-4a,5,7,8-tetrahydro-IH-pyrazolo[3,4-disoquinolinc-6(4H.)-carboxylate (0.25 g, 0.520 mm.ol) in dichloromethane (8 ml,) and trifluoroacetic acid (2 ml,) was stirred at room temperature for 90 minutes, then evaporated, azeotroping twice with toluene to give a brown oil.
This material was re-dissolved in dichloromethane (8 and diisopropylethylamine (0.454 ml.õ
2.60 mmol.) was added, followed by 4-fluorobenzene-l-sulfonyl chloride (0.121 g, 0.624 mmol), and the reaction mixture stirred at room temperature for 48 hours. The reaction mixture was then evaporated in vacuo and the residue purified by column chromatography on silica gel (gradient: 0 to 40% ethyl acetate in isohexane) to give a white solid (204 mg). Kting of this sample was purified by preparative HPLC (Varian, Acidic (0.1% Formic acid), Waters X.-Select Prep-C18, 5 gm, 19x.50 mm column, 25-80% acetonitrile in water) to afford (R)-(1-(4-fluoropheny1)-6-((4-fluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-111-pyrazolo[3,4-g]isoquinolin-4a-y1)(thiazol-2-yOmethanone as a pale yellow solid (45 nig). LCMS (Method F, ES-API): RT 2.58 min, ni-1-1I -538.9; 1H NMR (400 MHz, CDC,I3): 8 8.02 (d, 1111, J = 3.1 FIz), 7.75-7.70 (m, 2H), 7.68 (d, 111, .1 = 3.1 Hz), 7.45-7.40 (m, 211), 7.29 (s, 111), 7.20-7.11 (m, 4H), 6.53 (d, 111, J = 2.2 Hz), 5.49 (dd, 1H, J = 12.3, 2.0 Hz), 4.20 (d, 1H, J = 16.8 Hz), 3.93-3.86 (m, 1H), 2.94-2.83 (m, 2H), 2.74 (d, 1H, J = 12.4 Hz), 2.57-2.47 (m, 2H).
[03301 The following examples were similarly prepared from the appropriate intermediates:

Example 5A. (R)-(144-11E1 roDhenv1)-64(3-fluoroprienvOsulfonv1)-4.4a,5,6,7,8-hexahydro-1H-Dvrazolo13,4-21 isoct i olin-4a-v1)(thiazol-2-v1)methanone N.,S F
N I

[0331] LCMS (Method F, ES-API): RT 2.59 min, m+H = 539.0; IHNMR (400 MHz, CDC1.3):
6 8.06 (d, 1H, J = 3.2 Hz), 7.67 (d,111, J = 3.1 Hz), 7.53-7.45 (in, 2H), 7.45-7.39 (m, 3H), 7.30 (s, 11-1), 7.29-7.23 (m, 11-1), 7.19-7.13 (m, 211), 6.53 (d,1H, J = 2.1 Hz), 5.53 (dd, 1H, J = 12.2, 1.7 Elz), 4.22 (d, 1I-T, J = 17.1 Hz), 3.92-3.86 (in, 111), 2.94-2.81 (m, 211), 2.76 (d, 1H. J = 12.2 Hz.), 2.58-2.49 (m, 2H).
Example 5B. (R)-4-((.(1-(4-fluoroQheny1)-4a-(t hiazole-2-carbonA-4a,5,7,8-tetrahvdro-1H-.. pyrazolo13,4-disoattinolin-6(4H)-vi)sulfonvI)methvlbenzonitrile CN
N/
[0332] LCMS (Method F, ES-API): RI 2.36 min, m+11 = 560; 1H NMR (400 MHz, CDC13): 8 8.07 (d, 1H, J = 3.1 Hz), 7.66 (d, 1H, J = 3.1 Hz) 7.45-7.43 (m, 2H), 7.46-7.41 (m, 511), 7.32 (s, 1H), 7.20-7.16 (m, 2H), 6.55 (s, 1H), 5.47 (dd, 1H, j = 13.5, 2.0 Hz), 4.20 (d, 1H, J = 20 Hz), .. 4.13-4.06 (m, 211), 3.12 (d, 1H, j = 16 Hz), 2.86 (d, 1H, J = 20 Hz), 2.70-2.50 (m, 211), 2.44 (m, 1H).
Example 5C. (R)-(1-(4-fluorophenv1)-6-0-(trifluoromethvl)phenvI)sulfony1)-4,4a.54,7,8-hexahvdro-1H-nvrazolo13.4-alisonainalin-ila-v1)(pyridin-2-vDmethanone N
=-=.. 0 0 0 N N
c3 s [03331 LCMS (Method F, ES-API): RT 2.73 min, m+H = 583.2; 1HNMR (400 MHz, CDC13):
6.65-8.64 (1H, m), 7.94 (111, m), 7.89-7.78 (411, m), 7.63-7.59 (111, m), 7.47 (1H, ddd, J = 7.3, 4.8, 1.5 Hz), 7.44-7.40 (2H, m), 7.28 OH, s), 7.19-7.13 (211, m), 6.48 (1H, d, J = 2.2 Hz), 5.56 (III, dd, J = 12.4, 2.2 Hz), 4.26 (1H, d, J = 16.9 Hz), 3.89-3.85 (III, m), 2.91-2.79 (311, m), 2.58-2.48 (211, Example 5D. (R )-(1-(4-fluorophenv1)-6-((44tritluorom et hyl)nhenvOsulfonv1)-4,4a.5.6,7,8-h.exahvdro-111.-pvrazolo13A-glisoquinolin-4a-y1)(1-metliv-111-1 s2.4-triato1-5-v1)metlhanone N¨N/
0 0, p NS/L, [03341 1.,CMS (Method F, ES-API): RT 2.60 min, m+FI = 587.2; IFINMR (400 MHz, CDC13):
6 7.99 (111, d, J = 1.3 Hz), 7.83-7.81 (2H, m), 7.78-7.76 (2H, in), 7.44-7.41 (21-1, in), 7.33 (1H, s), 7.19-7.15 (2H, m), 6.56 OH, s), 5.36 (11-11, d, J = 12.8 Hz), 4.32 (11i, d, J = 17.1 Hz), 4.09 (311, s), 3.96-3.92 (1H, m), 2.89-2.79 (211, m), 2.71 (111, d, I = 12.8 Hz), 2.57-2.50 (2H, m).
Example 5E. (R)-41 44-fluoropheny1)-6-((4-(trifluoromethvl)phenv1)sulfonv11-4,4a.5.6,7.8-hexahvdro-111-pyrazolo13.4-disoquinolin-4a-v11(pyrazin-2-vI)nethanone i 0 --rs¨N

N ,..,........,.... C.) (:).µ µ p N/7-r" NJ'S iii srµl '-' --) j miirr CF3 Si F
[03351 LCMS (Method F, ES-API): RT 2.59 min, m+H = 583.8; 1H NMR (400 MHz, CDC1.3):
9.10 (1.H, d, J = 1.7 Hz), 8.79 (1H, d, J = 2.3 Hz), 8.62 (1H, dd., J = 2.3, 1.7 Hz), 7.83-7.81 (2H, in), 7.77-7.75 (2H, m), 7.44-7.41 (2H, m), 7.29 (1.H, s), 7.20-7.15 (2H. m), 6.51 (1F1, d, J = 2.1 5 114 5.39 (1171, dd, J = 12.4,2.3 Hz), 4.12 (1II, d, J = 16.9 Hz), 3.90-3.85 (11-1, m), 2.92-2.88 (2H, ni), 2.72(111, d, J = 12.4 Hz), 2.52-2.45 (2H, m).
Example 5F. (R)4144-fluorophe n 0-64(5- film ropy rid i n-3-1/1)sulfon v1)-4,4a,5,6,7.8-hex ahvdro-111.-pvrazolo[3.4-21isog nin oh ii.-4a-y1)(pyrid i n-2-vi)nulb a none q IN1-\S'F
N r_ L
' -J, ) I
'IA = --...- ie *
F
[03361 LCMS (Method F, ES-API): RT 2.35 min, m+H = 534.2; 1H NMR (400 MHz, CDC13): 8 8.73 (1.H, m), 8.67-8.65 (1F1, m), 8.60 (1H, d, J = 2.8 Hz), 7.89-7.82 (2H, m), 7.65 (1H, ddd, J = 7.6, 2.8, 1.8 HZ), 7.49 (1H, ddd, J = 6.8, 4.8, 1.8 Hz), 7.45-7.40 (2H, m), 7.29 (1H, s), 7.19-7.13 (2H, m), 6.51 (1H, d, .1 = 2.1 Hz), 5.60 (1H, dd, .1 = 12.4, 2.1 Hz), 4.26 (1H, d, J =
16.9 Hz), 3.92-3.88 (1H, m), 2.91-2.79 (311, m), 2.67-2.61 (1H, m), 2.55-2.50 (1H, m).
Example 5G. (11)-(1.-(4-fluoroptienvi)-64(3-11uoroyli envbsulfonv11-4.4a.5,6,7,8-hexahvdro-I H-pyrazo1o13,4-elisoauino11n-4a-vaur, ri din-2-v Oniethanone lzi i N
I -" 0 0 0 N

F

[03371 LCMS (Method F, ES-API): RT 2.56 min, m+H = 532.8; IHNMR (400 MHz, CDC13): 8 8.67 (1H, ddd, J = 4.7, 1.7, 0.8 Hz), 7.91-7.88 (1H, m), 7.85 (1H, dt, J = 7.4, 1.7 Hz), 7.50-7.36(611, m), 7.29(111, s), 7.27-7.22 (I.H, m), 7.19-7.13(211, m). 6.48 (111, d, J= 2.1 Hz), 5.55 (IH, dd., J = 12.4,2.1 Hz), 4.30(111, d, J = 16.9 Hz), 3.86-3.81 (1H, m), 2.91-2.73 (311, m), 2.54-2.47 (211, m).
Example 511.(R)-(1-f4-fltiorophenv1)-64(4-(1ri11tiorome1hvi)phenµl)sulfonv1)4,42.5,6,7,8-hexahvdro-1 H-Dvrazolo13.4-glisoquillolin-hla-v1)(5-methoxspyrishn-2-v1)methanolle Me0 N
N
N

[03381 I.CMS (Method F, ES-API): RT 2.76 min, m+H = 613.2; I H NMR (400 MHz, CDC-13): 8 8.72 (111, dd, J = 2.5, 0.6 Hz), 8.06 (111, dd, J = 8.8, 2.5 Hz), 7.95-7.93 (211, in), 7.81-7.79 (211, m), 7.47-7.42 (211, in), 7.41 (III, s), 7.22-7.16(211, m), 6.72 (111, dd, J = 8.8, 0.6 Hz), 6.44 (Ili, s), 4.59 (1H, dd, J= 11.1, 1.7 Hz), 3.96 (311, s), 3.90-3.86 (1II, m), 3.73 (111, d, J =
17.8 Hz), 2.79 (I H, d, J= 17.8 Hz), 2.56 (1H, d, J = 11.1 Hz), 2.53-2.46 (1H, m), 2.31-2.20 (2H, m).
Eva rople 51. (R)-(144-11uorophenv1)-6-044trilltioromethyflphenvI)staonvi)-4,-la.5.6,7.8-11('S ail Vd ro-1Ã1-nvrazolo13.4-glisoquino1iQ--ia-v1Athiatol-5-vi)methanone lz-12 .

.. "----..) I
1---, F
[03391 LCMS (Method F, ES-API): RT 2.56 min, m+H = 589.1; 1H NMR (400 MHz, CDC13): 8 8.95 (111, d, J = 0.5 Hz), 8.48 (III, d, J = 0.5 Hz), 7.94-7.92 (211. m), 7.81-7.79 (2H, in), 7.47-7.42 (2H, m), 7.37(111, s), 7.23-7.17 (211, m), 6.55 (111, s), 4.62 (1H, dd, J= 11.5, 1.9 Hz), 3.93-3.88 (111, m), 3.34 (111, d, J = 17.6 Hz), 2.83 (111, d, J = 17.6 Hz), 2.61 (1H, d, J =
11.5 Hz), 2.58-2.42 (3H, m).
Example 51 (R)41-(4-11tioraphenv1)-645-fluoronvridia-3-y)sulfon yl)-4,4a,5,6,7.8-hexah.vdro-1H-pvrazolol3A-gl i sof.] uitioli n-4a-v1)(thiato1-2-v1)inet ha none S
F
NI, I1 I
N ---;-?""----""
N
(----- 1 F
103401 LCMS (Method F, ES-API): RT 2.35 min, ml.F1 ,=== 540.
Example 6. (R)-(144-fluoropheav1)-64(4-(pyrrolidiii-l-s.1)phenvi)sulfonvi)-4,4a.5,6,7,8-hexahvdro-1H-pvrazolo13.4-21isoquitiolin-4a-v1)(thiazoi-2-v1)methanone S' .,..;., ..õ......
F

193411 A solution of pyrrolidine (0.046 rnL, 0.557 minol) and (R)-(1-(4-fluoropheny1)-644-fluorophenyl)sulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(thiazol-2-yOmethanone (0.1 g, 0.186 mmol) in N-methylpyrrolidine (2mL) was stirred at 50 C in a sealed vial for 6 hours, then allowed to stand at room temperature for 72 hours. The reaction mixture was then stirred at 100 C for an additional 5 hours, cooled to room temperature, and purified directly by preparative HPLC (Varian, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 gm, 19x50 mm column, 50-70% acetonitrile in water) to afford (11)-(1-(4-fluorophenyl)-6-04-(Pyrrol id in- 1 -yl)phenyl)sulfony1)-4,4a,5,6,7,8-hexabydro-111-pyrazolo[3,4-0isoquinolin-4a-y1)(thiazol-2-ypmethanone as a pale yellow solid (58 mg). LCMS (Method F, ES-API): RI 2.81 min, m+H = 590.0; 1H NMR (400 MHz, CDC13): 6 8.02 (d, 1H, J = 3.1 Hz), 7.62 (d, 11, J = 3.1 Hz), 7.54-7.50 (m, 2H), 7.45-7.40 (m, 2H), 7.28 (s, 1H), 7.219-7.12 (in, 2H), 6.50-6.45 (m, 3H), 5.46 (dd, I H, J = 12.1, 2.0 Hz), 4.21 (d, 111, J = 16.8 Hz), 3.86-3.80 (m, 1H), 3.35-3.30 (m, 4H), 2.92-2.81 (m, 2H), 2.64 (d, 1H, J = 12.2 Hz), 2.52-2.36 (m, 2H), 2.07-2.01 (m, 4H).
103421 The following examples were similarly prepared from the appropriate intermediate:
Example 6A. (R)-(1-(4-fluaraphenv1)-643-(pyrrolidin-1-v1)phenyl)sulfonv1}-4.4a.5,6,7,8-hexahydro-1H-pvrazoloi3,4-glisoquinolin-4a-y1)(thiazol-2-y1)methanone S' FP
N
N
N' F
103431 LCMS (Method F, ES-API): RI 2.88 min, m+H -- 590.1; 1H NMR (400 MHz, CDC13):
6 8.04 (d, IH,J =2.8 Hz), 7.63 (d,1H, J = 3.2 Hz), 7.45-7.40 (m, 2I1), 7.33-7.24 (m, 3II), 7.19-7.10 (m, 2H), 6.99-6.94 (m, 1H), 6.65 (dt, 1H, J = 8.0, 2.3 Hz), 6.50 (d, 1H, J = 2.4 Hz), 5.46 (dd. 1H, J = 12.7, 2.1 Hz), 4.22 (d, 1H, J = 16.6 Hz), 3.91-3.81 (m, 1H), 3.33-3.23 (m, 4H), 2.94-2.83 (m, 211), 2.76 (d, 1H, J = 12.4 Hz), 2.54-2.46 (m, al), 2.06-2.01 (m, 4H).
Example 7. (R)-(1-(4-fluorophenv1)-64(5-(piperidin-l-v1)pyridin-3-y1)sulf0011)-4,4a..5.6,7,8-hexahvdro- 1 H-pyrazoloj3.4-alisoquitiolin-4a-v1)(thiazol-2-vbinet1ianone s 0 0õ0 N I N
\I N".
103441 A mixture of (R)-(1-(4-fluoropheny1)-64(5-fluoropyridin-3-ypsulfony1)-4,4a,5,6,7,8-hcxahydro-1H-pyrazolo[3,4-g]isoquinolin-40-y1)(thiazol-2-y1)methanonc (100 mg, 0.185 mmol) and piperidine (47 mg, 0.56 mrriol) in N-methylpyrrolidine (1 mL) was heated at 100 C for 6 hours. The mixture was cooled and the reaction mixture was purified by preparative HPLC
(Gil.son, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 ttm, 19x50 mm column, 5-95% acetonitrile in water) to give (R)-(1-(4-fluoropheny1)-64(5-(piperidiri-1-Apyridin-3-ypsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-y1)(thiazol-2-y1)methanone as a white solid (35 mg). LCMS (Method F, ES-API): RI 2.64 min, m+H = 605;
1H NMR. (400 MHz, CDCI3): 8 8.39 (d, 1H, J = 3.0 Hz), 8.27 (d, I H, J = 2.0 Hz), 8.05 (d, 1H, J
- 3.0 Hz), 7.65 (d, IH, J= 3.0 Hz), 7.54-7.41 (m, 2H), 7.31-7.30 (m, 2II).
7.19-7.14 (m, 2H), 6.53 (d, I H, J 2.0 Hz), 5.51 (dd, 1H, J = 12.0, 2.0 Hz), 4.21 (d, 11-1, J =
17.0 Hz), 3.90-3.86 (m, 111.), 3.27-3.25 (m, 411), 2.91-2.81 (m, 31-1), 2.61-2.52 (m, 21-1), 1.75-1.56 (m, 614).
[03451 The following examples were similarly prepared from the appropriate intermediate:
Example 7A. (R)-( I -(4-fluorophen.v1)-64(5-(pyrrolidin-1.-vtawridia-3-vDsulfonv1)-4.4a,5.6.7,8-hexahvd ro- 1H-nyrazolo [3,4-el isoa ui nolin-4 a-v11(thiazol-2-v1)m eth anon e (11 s 0õ0 N I N
[03461 LCMS (Method F, ES-API): RI 2.49 min, m+H = 591; 1H NMR (400 MHz, CDCI3): 8 8.18 (1H, d, J = 2.0 Hz), 8.06 (1H, d, J = 3.0 Hz.), 8.04 (IH, d, J 3.0 Hz), 7.65 (1K, d, J = 3.0 Hz), 7.43 (211, dd, J 9.0, 5.0 Hz), 7.29 (IH, s), 7.19-7.14 (2H, m), 6.95-6.93 (111, m), 6.53 (111, d, J = 2.0 Hz), 5.50 (1H, dd,J = 12.0, 2.0 Hz), 4.2 (1H, d, J = 17.0 Hz), 3.92-3.88 (1H, m), 3.33-3.28 (4H, m), 2.90-2.82 (3H, m), 2.62-2.51 (2H, m), 2.09-2.04 (411, m).
Example 8. (R)-(1-(4-fluorophenv1)-64(64Dvrrolidin-1-ybpyridin-3-thsulfonv1)-4,4a.5,6.7.8-hexahydro-11-1-vvrazo1013,4-2lisoquinolin¨la-vVovridin-2-811ineiltanone N

N-N
N.' 0 [03471 A solution of (R)-(6-((6-chloropyridin-3-yl)sulfony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-IFI-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-Amethanone (100 nig, 0.182 mmol) and pyrrolidine (37.9 I, 0.455 mmol) in acetonitrile (2 mL) was stirred in a sealed vial at 40 C
for 1 hour. The cooled reaction mixture was then purified directly by preparative HPLC (Waters, A.cidic (0.1% Formic acid), Waters X-Select Prep-Cl 8, 5 gm, 19x50 mm column, 5-95%
acetonitrile in water) to afford (R)-(1-(4-fluoropheny1)-6-((6-(pyrrolidin-1-yppyridin-3-ypsulfonyl)-4,4a,5,6,7,8-hexahydro-IFI-pyrazolo[3,4-g]isoquinolin-4a-y1)(pyridin-2-y1)methanone as a white solid (29 mg). LCMS (Method F, ES-API): RI 2.48 min, m-i-F1 = 585.3;
IFE NMR (400 MHz, CDCI3): 8 8.63-8.61 (111, m), 8.43(111, d, J = 2.4 Hz), 7.89-7.87 (1.FI, m), 7.80 (1H, dt, J- 7.6, 1.8 Hz), 7.58 (1171, dd. J ¨ 9.0, 2.4 Hz), 7.45-7.41 (3F1, m), 7.28(111, s), 7.19-7.13 (2H, m), 6.47 (111, d, J = 2.1 Hz), 6.22 (111, d, J = 9.0 Hz), 5.46 (1H, dd. J= 12.2, 2.1 Hz), 4.27 (1H, d, J - 16.9 HZ), 3.83-3.79 (III, m), 3.52-3.45 (41I, in), 2.90-2.76 (21I, in), 2.68 (111, d,1 12.3 F17), 2.51-2.45 (2H, m), 2.06-2.04 (4H, m).
Example 9. t (R)-1-(4-fluorophenv1)-6-((64(R)-3-fluoronvrrolidin-l-vihnritlin-vi)suliony11-4,4a.5.6,7.8-hexalt dro-11-1-MTai.01013,4-disoquinoliti-4a-v1)(thiazol-2-Almethanont zi 6 f-N
\s).0 0 N
N
[03481 A mixture of (R)-(6-((6-chloropyridin-3-ypsulfony1)-1-(4-fluorophenyl.)-4,4a,5,6,7,8-hexahydro-tH-pyrazolo[3,4-g]isoquinolin-4a-y1Xtbiazol-2-Amethanone (92 mg, 0.165 mmol) and (R)-3-fluoropyrrolidine.HC1 (41.6 mg, 0.331 mmol) in N,N-dimethylformamide (2 mL) was stirred in a sealed vial at 40 C for 1 hour, then at 55 C for a further 2 hours. The cooled reaction mixture was then purified directly by preparative HPLC (Waters, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 um, 19x50 mm. column, 5-95% acetonitril.e in water) to afford ((R)-1-(4-fluoropheny1)-6-06-((R )-3-fluoropyrrolidin-l-yl)pyridin-3-yl)sulfony1)-4,4a,5,6,7,8-hexahydro- I H-pyra.zo1o[3,4-glisoquinolin-4a-y1)(thiazo1-2-y1)methanone as a white solid (17 mg). LCMS (Method F, ES-API): RT 2.39 min, mill = 609.2; 111 NMR
(400 MHz, CDC13): 5 8.46 (1H, d, .1= 2.6 Hz), 7.95 (1171, d, J = 3.1 Hz), 7.64(111, dd, J = 9.0, 2.4 HZ), 7.61 (1H, d, J = 3.1 Hz), 7.45-7.40 (2H, m), 7.28 (114, s), 7.19-7.13 (2H, m), 6.52 (1.H, d, J = 2.3 Hz), 6.27 (1H, d, J = 9.1 Hz), 5.48-5.35 (2H, m), 4.17 (11i, d, J = 16.8 Hz), 3.92-3.59 (6H, m), 2.92-2.82 (211, m), 2.77 (1H, d, .1= 12.3 Hz), 2.59-2.42 (311, in).
Example 10. ( R )-(1-(4-fluorop en v1)-644-(revrralid in-I-v1)phenvI)su Ifo n vI)-4,4a,5.6,7,8-llexahvdro-1H-pyrazolo13.4-alisoquitiolin-4a-v1)(Dvridin-2-.thmethanone N

"S*

sls1 F
[03491 A solution of pyrrolidine (0.065 mL, 0.783 m.mol) and (R)-(1-(4-fluorophenyl.)-644-fluorophenyl)sulfony1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-yl)methanone (183 mg, 0.261 mmol) in N-methylpyrrolidine (2 mL) was stirred in a sealed vial at 100 C for 22 hours. The cooled reaction mixture was then purified directly by preparative HPLC (Waters, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 p.m, 19x50 mm column, 5-95% acetonitrile in water) to afford (R)-(1-(4-fluoropheny1)-6((4-(pyrrolidin-1 yl)phenyl)sulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-y1)(pyridin-2-.. yl)methanone as an off-white solid (52 mg). LCMS (Method F, ES-API): RT
2.78 min, mtH =
584.3; 1H NMR (400 MHz, CDC13): 6 8.63-8.62 (1H, m), 7.89 (1H, di, J = 8.0, 1.2 Hz), 7.81 (1H, td, J = 7.5, 1.8 Hz), 7.51-7.47 (2H, m), 7.46-7.41 (3H, m), 7.28 (1H, s), 7.18-7.12 (2H, m), 6.48-6.45 (311, m), 5.41 (1H, dd, J = 12.2,2.1 Hz), 4.31 (11-1, d, J = 16.9 Hz), 3.80-3.76(111, m), 3.33-3.30 (41I, m), 2.88 (1H, d, J = 16.9 Hz), 2.85-2.76 (1H, m), 2.61 (1H, d, .1= 12.1 Hz), 2.45-.. 2.35 (2H, m), 2.07-2.01 (4H, m).
[03501 The following examples were similarly prepared from the appropriate intermediate:
Example 10A. (R)-(144-fluorophenv1)-64(54pipetidin-1-v1)pvridin-3-µ71)sulfon .1)-4,4a.5,6,7,8-hexahvdro-1H-pvrazolal3.4-g1 ISOauinalin-41a-y1)(py ridin-2-yl)meth a none N
0 00 rTh N, N =-=
[0351] I.,CMS (Method F, ES-API): RT 2.56 min, m+H = 532.8; 1HNMR (400 MHz, CDC13): 6 8.65 (1H, ddd, J = 4.7, 1.7, 0.8 Hz), 8.36 (1H, d, J = 2.8 Hz), 8.25 (1H, d, J = 1.7 Hz), 7.90-7.87 (1H, m), 7.83 (1H, dt, J = 7.4, 1.7 Hz), 7.49-7.41 (311, m), 7.29-7.28 (211, m), 7.19-7.13 (211, m), 6.49 (1H, d, J= 2.1 Hz), 5.52(11-1, dd, j =12.4, 2.1 Hz), 4.28 (1H, d, J = 16.9 Hz), 3.86-3.82 (1H, m), 3.25-3.23 (4H, m), 2.92-2.78 (3H, m), 2.59-2.48 (2H, m), 1.74-1.61 (6H, m).
EVa ntple 10B. (R)-(144-fluorophenv1)-64(5-(pyrro1idia-1 -8 Opyridin-3-y 1)sulfonv1)-4,4a.5,6..7,8-hex a Its d ro-111-p% razo1oi3,4-glisoquino1in-4a-v1)(nvridin-2-v1)ntethanotte z-18 0 0,µ,e0 4-) r N N
'N
[03521 LCMS (Method F, ES-API): RT 2.42 min, m+H = 585.3; 1H NMR (400 MHz, CDC13): 8 8.63 (1H, ddd, J = 4.7, 1.8, 0.9 Hz), 8.16 (1H, d, J = 1.8 Hz), 8.02 (111, d, J = 3.0 Hz), 7.89-7.86 (1H, m), 7.81 (111, td, J = 7.5, 1.8 Hz), 7.48-7.40 (3H, m), 7.28 (lH, s), 7.19-7.13 (2H, .. m),6.91 (111, dd, J = 2.6, 2.1 Hz), 6.48 (1II, d, J = 2.1 Hz), 5.50 (1H, dd, = 12.2,2.1 Hz), 4.27 (114, d, J = 17.0 Hz), 3.87-3.83 (1H, m), 3.32-3.26 (411, m), 2.91-2.79 (311, m), 2.59-2.49 (211, m), 2.08-2.04. (41-1, m).
Example 11. (R)-(1-(4-flooronhenv1)-6-0-(trifluorontetlutl)rthens1)sulfouvl)-4..4a,5,6.7,8-hexahvtlro-111-pyrazolo13.4-glisoquinolin¨ta-vlythiatul-4-1.13rntihanonc N
S\LO

N'41 Ns , I

103531 A solution of (R)-tert-butyl 1-(4-fluoropheny1)-4a-(2-(trimethylsilyl)thiazole-4-carbony1)-4a,5,7,8-tetrahydro-IH-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate (76 mg, 0.103 mmol) in 4 M HCl/dioxane (3 niL) was stirred at room temperature for 1 hour.
The solvent was removed in vacuo (azeotroping twice with toluene (-4 mi.)) to give a dark orange oil. This was dissolved in dichloromethane (3 and 4-(trifluoromethyObenzene-1-sulfonyl chloride (30.3 mg, 0.124 mmol) was added followed by diisopropylethylamine (90 Id, 0.516 mmol). The reaction mixture was stirred at room temperature for 0.5 hour. The solvent was removed in maw to give a dark orange oil. The crude product was purified by column chromatography on silica gel (gradient:0-40% ethyl acetate in isohexane) to afford (R)41-(4-fluoropheny1)-6-04-(trifluoromethyl)phenypsulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-yl)(thiazol-4-yOmethanone as a white solid (44 mg). LCMS (Method F, ES-API):
RI 2.65 min, m+H = 589.2; 1H NMR (400 MHz, CDCI3): 8 8.86 (1H, d, J = 2.1 Hz), 8.23 (1H, d, i = 2.1 Hz), 7.84-7.82 (2H, m), 7.74-7.72 (2H, m), 7.45-7.40 (2H, m), 7.28 (1H, s), 7.19-7.13 (2H, m), 6.51 (1H, d, J = 2.1 Hz), 5.48 (111, dd, J = 12.5,2.1 Hz), 4.15 (1H, d, J = 16.6 Hz), 3.92-3.87 (1H, m), 2.93-2.85 (2H, m), 2.72 (11i, d, J = 12.6 Hz), 2.56-2.49 (2H, m).
103541 The following examples were similarly prepared from the appropriate intermediates:
Example 11A. (R)-(6-04-ehlorophenvlisulfonv1)-144-fluorophenv1)-4,4a,5.6.7.8-hexahl dro-111-pyrazolo13.4-disottainolin-4a-v1)(pyridin-2-v1)methanone IN Ali CI

:b N
NI I
[03551 LCMS (Method F, ES-API): RT 2.74 min, m+H = 548.9; 1H NMR (400 MHz, CDC13): 8 8.61 (1H, ddd, J = 4.7, 1.7, 0.9 Hz), 7.88 - 7.81 (2H, m), 7.62 -7.58 (2H, m), 7.51 7.37 (5H, m), 7.28 (1H, s), 7.20 - 7.12 (2H, m), 6.49 (1H, d, J = 2.1 Hz), 5.51 (1H, dd, J = 12.2, 2.1 Hz), 4.28 (1H, d, J = 16.9 Hz), 3.89 - 3.80 (1H, m), 2.92 - 2.77 (2H, m), 2.74 (1H, d, i = 12.2 Hz), 2.54 - 2.46 (2H, m).
La ample I I It (R)-(144-fluorovhenvi)-6-(0-methoxv-3-methylphenvOsulfonvi)-4,4a,5,6,7.8-13exairk ridin-2-vipmetbanom, -"7"N ,r0Me . 0 0 N
Ns j j N
Si [0356] LCMS (Method F, ES-API): RI 2.69 min, m-1--E1 = 559.0; 1H NMR (400 MHz, CDC13): 6 8.62 (1H, ddd, J = 4.7, 1.7, 0.9 Hz), 7.89 - 7.86 (1H, m), 7.85 -7.79 (1H, m), 7.52 (1H, dd, J = 8.6, 2.1 Hz), 7.45 - 7.41 (4H, m), 7.28 (1H, m), 7.19 - 7.12 (2H, m), 6.81 (1H, d, J =
8.6 Hz), 6.47 (1H, d, J = 2.1 Hz), 5.47 (111, dd, J = 12.1,2.1 Hz), 4.30(1H, d, J = 17.0 Hz), 3.88 - 3.79 (4H, m), 2.90- 2.77 (2H, m), 2.67 (1H, d, J = 12.1 Hz), 2.51 - 2.38 (2H, m), 2.19 (3H, s).
Example 11 C.. (11)-(6-((3-ch1oro-4-methoxyphenvI)sulfonv1)-1-(4-1111 oropheny1)-4,4a15t6,741-hexahvdro-111-0-razolo134-disthrtuino1in-4a-y1)(pyri(110-=2-1,1)met13 an o n e N
µSµ CI
N"
N I
'14 =
[0357] LCMS (Method F, ES-API): RI 2.67 min, m+FI = 578.9; 1H NMR (400 MHz, CDC13): 6 8.63 (iii, ddd, J = 4.7, 1.7, 0.9 Hz), 7.89 - 7.78 (2H, m), 7.67 (111, d, J = 2.2 Hz), 7.57 (111, dd, J = 8.7, 2.2 Hz), 7.48 - 7.41 (311, m), 7.28 (111, m), 7.18 -7.13 (21-1, m), 6.91 (111, d, 8.7 Hz), 6.48 (111, d, J = 2.1 Hz), 5.50(11-1, dd, J = 12.2. 2.1 Hz), 4.28(111, d, J = 16.9 Hz), 3.94 (311, m), 3.87- 3.79 (111, m), 2.91 - 2.78 (211, m), 2.74 (11-1, d, J = 12.2 Hz), 2.54 - 2.47 (211, m).
Example 11D. )-(643-fluoro-4-methoxvohenvi)sulfo ny1)-1-(4-flu oroph 1 5 lwvaii% dro-1111-0-razo1o1.3.4-klisoquinolin-4a-ylOvridin-2-µ1)me thanoae N
0 0õ0 F
NI Ni 111111-11 OMe [0358] LCMS (Method F, ES-API): RI 2.57 min, m-1-H = 563.2; 1H NMR (400 MHz, CDC13): 68.64 (1H, ddd, J = 4.8, 1.7, 0.8 Hi), 7.90-7.87 (1H, m), 7.83 (1H, dt, J = 7.5, 1.7 Hz), 7.48-7.41 (4H, m), 7.37 (1H, dd, J = 10.3,2.3 Hz), 7.28 (1H, s), 7.19-7.13 (2H, m), 6.99-6.95 (1H, m), 6.48 (1H, d, J = 2.1 Hz), 5.49 (1H, dd, J = 12.1,2.1 Hz), 4.29 (1H, d, J = 16.9 Hz), 3.93 (3H, s), 3.85-3.80 (1H, m), 2.91-2.77 (2H, m), 2.72 (1H, d, J = 12.2 Hz), 2.53-2.46 (2H, m).
Example 11E. (R)-(64(2-11tiore-4-methylphenyl)su1fonv1)-1-(4-fluoropht,riv1)-4,4a,5,6,7,8-liemt11µ tiro- I 1-1 -p vrazolof 3A-21isopuinoin-4a-v1)(0vridin-2-yhmet Ilan mit I Q,0 F
:
N,/ I N
[03591 LCMS (Method F, ES-API): RT 2.67 min, m+H = 547.2; 1H NMR (400 MHz, CDC13): 6 8.63 (111, ddd, J = 4.7, 1.6, 1.0 Hz), 7.85-7.82 (1H, m), 7.80 (1H, dt, J = 7.3, 1.8 Hz), 7.59-7.55 (1H, m), 7.46-7.41 (3H, m), 7.28 (1H, s), 7.19-7.13 (2H, m). 6.95-6.90(211, m), 6.50 (1H, d, J = 2.2 Hz), 5.57 (1H, dd, J = 12.8, 1.8 Hz), 4.29 (1H, d, J = 16.9 Hz), 3.95-3.91 (1H, m), 2.97 (1H, dd, 12.9, 1.1 Hz), 2.91-2.79 (211, m), 2.74-2.68 (1H, m), 2.51-2.47 (1H, m), 2.37 (3H, s).
Example 11F. (R)-( 1-( 4-11 no roph en v1)-6-(m-tolvIsulfonv1)-4,4a.5,6,7,$-hexahvdro-1H-pyrazolo13,4-ti, lisp() ui no 11 n -4a-N 1)(th azol-4-vbm et ti a n one S. N

NI I N' 1101 %N
103601 LCMS (Method F, ES-API): RT 2.57 mm, m+H = 535.1; 1H NMR (400 MHz, CDC13): 6 8.88 (1H, d, J = 2.4 Hz), 8.25 (1H, d, J = 2.4 Hz), 7.52-7.50(211, m), 7.45-7.40 (2H, m), 7.37-7.36 (2H, m), 7.28 (1H, s), 7.19-7.13 (211, m), 6.49 (111, d, J = 2.3 Hz), 5.45 (111, dd, J
= 12.1, 2.3 Hz), 4.18 (111, d, J = 16.9 Hz), 3.87-3.83 (1H, m), 2.92-2.82 (2H, m), 2.63 (1H, d, J =
12.4 Hz), 2.50-2.39 (511, m).

Example I IC. (R)-3-(( I -(41-fluorophenv1)-4a-picolinovi-42,5,7,8-tetralivdro-pvrazolo I 3.4-tzl is 00 ninolin-6(411)-vbsulfonyl)benionitrile CN
N
N
[03611 LCMS (Method F, ES-API): RT 2.48 min, m+H = 540.0; 1H NMR (400 MHz, CDC13): 6 8.68 - 8.66 (1H, m), 7.93 - 7.78 (5H, m), 7.60 (1H, td, J = 7.8, 0.6 Hz), 7.50 (1H, ddd, J = 6.8,4.8, 2.2 Hz), 7.45 - 7.39 (2H, m), 7.28 (1H, m), 7.19 - 7.13 (2H, m), 6.50 (1H, d, J = 2.1 Hz), 5.60 (1H, dd, J = 12.4, 2.1 Hz), 4.26 (1H, d, J = 16.9 Hz), 3.92 - 3.83 (1H, m), 2.90- 2.78 (3H, m), 2.58 - 2.49 (2H, m).
Example 1l-I. (RI.-(6.-(14=-=iditi aoromethoxv)phenylIsulfonv1)-1-(4.-Iluoroplienv1)-41,4a.5,6.7,8-I 0 hexativdro-111-pvrazolol:3.4-glisociainolin-4a-v1)(pyridin-2-vi)methanone 'N
o\N
N/7-1211-S'N-IN') -`f [03621 LCMS (Method F, ES-API): RT 2.62 min, m+FI = 581.2; 1HNMR (400 MHz, CDCI3): 6 8.62 (1H, ddd, J = 4.8, 1.7, 0.8 Hz), 7.89-7.87 (1H, m), 7.83 dt, J = 7.5, 1.7 Hz), 7.71-7.68 (2H, m), 7.49-7.40 (3H, m), 7.28 (1H, s), 7.19-7.13 (4H, m), 6.57 (iH, t, J= 72.4 Hz), 6.48 (1H, d, J - 2.3 Hz), 5.52 (1H, dd, J = 12.2, 2.1 Hz), 4.28 (1H, d, J -16.9 Hz), 3.86-3.82 (1H, m), 2.90-2.78 (2H, m),2.74 (1H, d, J= 12.2 Hz), 2.54-2.46 (2H, in).
Example 111. (11)-(144-fluoroplieny1)-643-(trifhwrometlom )phenvpsu1fmtv1)-4,4a,5.6..7,8-11eNalivdro-Il1-pvraz01013.4-glisofluinolin4a-v1)(pyri1ia-2-thmel1za8ifine i 0 sp N I NY is oc,3 [03631 LCMS (Method F, ES-API): RT 2.79 min, m+H = 599.2; 1H NMR (400 MHz, CDC13): 8 8.67 (1H, ddd, .1= 4.8, 1.7, 0.8 Hz), 7.91-7.88 (1H, m), 7.84 (1H, dt, J = 7.5, 1.7 Hz), 7.64-7.62 (1H, m), 7.54-7.47 (3H, m), 7.45-7.38 (3171, m), 7.29(111, s). 7.19-7.13 (2H, m), 6.49 (111, d, J = 2.3 Hz), 5.55 (111, dd, J = 12.4,2.2 Hz), 4.29 (1H, d, J = 16.9 Hz), 3.86-3.81 (111, m), 2.91-2.74 (311, m), 2.54-2.47 (2171, m).
Example Iii. (R)-(6-((3,5-difluorophenvI)su Ifony1)-1 -(4-fluorophenv1)-4,4a..5,6,7,8-h ex ahvdro-1 11-pyrazolo[3.4-glisoQuinolin-4a-v1)(pyridin-INI)metbanone LjLN
0 op N
RN] F
[03641 LCMS (Method F, ES-API): RT 2.67 min, m+H = 551.2; 1H NMR (400 MHz, CDC13): 8 8.67 (iH, ddd, J = 4.7, 1.7, 0.8 Hz), 7.88 (1H, ddd, J = 7.9, 1.5, 1.0 Hz), 7.84 (1H, dt, J = 7.3, 1.7 Hz), 7.48 (1H, ddd, J = 7.4,4.7, 1.5Hz), 7.46-7.41 (2H, m), 7.29 (1H, s), 7.22-7.13 (41-1, m), 6.98 (1H; tt, J = 8.5, 2.3 Hz), 6.49 (1H, d, i = 2.1 Hz), 5.36 (1H, dd,1 = 12.3, 2.1 Hi), 4.28 (1H, d, J = 16.9 HZ), 3.87-3.82 (1H, in), 2.92-2.78 (3H, m), 2.62-2.55 (1H, m), 2.53-2.48 (1H, m).
Example 11K. (R)-(1-(4-fluorophenv1)-6-losyl-4,4a.5.6,7,8-hexaltvdro-11171-pvraz01013.4-glisoominolin-4a-v1)(thiatal-4-µ1)mellianone fis¨N
S 0 0, rj-7Y
N

[03651 I,CMS (Method F, ES-API): RT 2.56 min, m+H = 535.0; 1H NMR (400 MHz, CDC13): 8 8.86 (111, d, J = 2.2 Hz), 8.24 (111, d, J = 2.2 Hz), 7.59 - 7.55 (211, m), 7.47 - 7.39 (211, m), 7.27 - 7.25 (311, in), 7.19 -7.12 (211, m), 6.49 (111, d, J = 2.0 Hz), 5.43 (1H, dd, J =
12.3, 2.0 Hz), 4.17 d, J= 16.9 Hz), 3.84(111, ddt, J.= 8.5, 4.4, 2.0 Hz), 2.91 -2.80 (211, m), 2.61 (1H, d, J= 12.3 Hz), 2.49 - 2.37 (5B, m).
Example 1111. (R)464(3-(difluorometlioxv)phenvI)sulfonv1)-1-(4-11iioropheitv1)-44a,5,6,7,8-hexalivdro-1li-pyrazolo[3,4-glisoquinolin-4a-v11(pvritiiti-2-si an on e =-*" N
JL-0 0õ0 Ni I N
F
) [03661 LCMS (Method F, ES-API): KT 2.63 min, m+1i = 581.2; 1H NMR (400 MHz, CDC13): 8 8.65 (1H, ddd, J = 4.8, 1.7, 0.8 Hz), 7.89-7.87 (1H, m), 7.83 (1H, dt, J = 7.5, 1.7 Hz), 7.56-7.53 (1H, m), 7.49-7.40 (5H, in), 7.31-7.28 (2H, in), 7.19-7.13 (2H, m), 6.55 t, J =
72.7 Hi), 6.48 (1H, d, J = 2.3 Hz), 5.52 (1H, dd, J = 12.2, 2.1 Hi), 4.28 (1H, d, J = 16.9 Hi), 3.86-3.81 (1H, m), 2.90-2.75 (3H, in), 2.55-2.46 (2H, in).
Example ii M. (R)-(64(3,4-di mei 1'1/When vi)su I fon )-1-(4411ftoronhenv1)-4,4a,5,6,7,8-hexahvdro-th-nyrazolol3A-glisoq uenolm4a-v1)(Pvriden.2-1,1)methamone NXfO
J
N
[03671 LCMS (Method F, ES-API): RT 2.76 min, m+H = 543.0; 1H NMR (400 MHz, CDC13): 8 8.64 (1H, ddd, J = 4.8, 1.7, 0.9 Hz), 7.92 - 7.80 (2H, m), 7.49 -7.39 (5H, m), 7.28 (1H, s), 7.20 -7.13 (3II, m), 6.46(111, d, J = 2.1 Hz), 5.47 (1H, dd, J =
12.2, 2.1 Hz), 4.30 d, J = 17.0 Hz), 3.83 - 3.79 (111, m), 2.91 - 2.71 (2I1, m), 2.67 (111, d, J =
12.2 Hz), 2.50 - 2.38 (214, m), 2.28 (6H, s).
Example 11N. (R)-(6-((3,5-dimethviphenvi)suirmsti)-1-(4-filwropheny1)-4,4%.5,6:748-h ex ahvd ro-III-Dvrazoloi3A-glison ulna n-4a-v1)(ovridin-2-v1)tnetbanone L)LN

N* I N 110 N
[03681 LCMS (Method F, ES-API): RT 2.78 min, m+El = 543.0; 1H NMR (400 MHz, CDCI3): 8 8.65 (iH, ddd, J = 4.8, 1.7, 0.9 Hz), 7.90-7.88 (1H, m), 7.83 (1H, dt, J = 7.5, 1.7 Hz), 7.49-7.40 (3H, m), 7.28 (3H, m), 7.19-7.13 (3H, m), 6.47 (1H, d, J = 2.3 Hz), 5.48 (1H, dd, J
12.2, 2.1 Hz), 4.30 (1H, d, J = 16.9 Hz), 3.83-3.79 (1H, m), 2.90 (1H, d, J =
16.9 Hz), 2.87-2.78 (1H, m), 2.70 (1H, d, J = 12.3 Hz), 2.50-2.42 (2H, m), 2.34 (6H, m).
Example 110. (R)(I44-11aoroahenv1)-6-((6-methylpyridin-2-vbsulfo v1)-4,4a,5,6,7,8-hexahvdro-111-pyrazolo[3.4-alisopuinolin-42-11)(nvridin-2-villnethanone ---"rs¨N

, N--f r'N'il-N
L-J I
N -''.
r--..
,s-py F
[03691 LCMS (Method F, ES-API): RT 2.46 min, m+H = 530.1; 1H NMR. (400 MHz, CDC13): 8 8.65 (1H, ddd, J = 4.7, 1.6, 1.0 Hz), 7.85-7.78 (2H, m), 7.69-7.65 (1H, m), 7.59-7.57 (111, m), 7.48-7.42 (31-1, m),7.29 (III, s), 7.27-7.25 (1H, m), 7.19-7.13 (2H, m), 6.51 (1H, d, 1. =
1.4 Hz), 5.62 (1H, dd, J = 12.9, 2.0 Hz), 4.31 (III, d, J = 16.9 Hz), 4.00-3.96 (1.H, m), 3.19 (111, d, J = 13.0 Hz), 2.95-2.91 (31-1, m), 2.59 (3H, s), 2.50-2.46 (11-1, m).
ENample 11P. (R)-(6-((3..4-di fluorophenv1)sul fonv1)-1-(4-fluorophen µ1)-4,4a,5,6,7,8-h ex a h vd ro-11l-pvrazolo13.4-g1 i soquinolin-4a-y1)(pvridi n-2-vi)neth anon e N
/1:1 4- N v' F
N=-:..--*".:"A"-...-- -.'" - F
lit F
[03701 LCMS (Method F, ES-API): RT 2.65 min, mill = 551.1; 1H NMR (400 MHz, CDC13): 8 8.63 (1.H, ddd, 1 = 4.8, 1.7, 1.0 Hz), 7.88 (1H, ddd, J = 7.9, 1.7, 1.0 Hz), 7.84 (1H, dt, J = 7.3, 1.7 Hz), 7.52-7.40 (5H, m), 7.28 (1H, s), 7.24-7.22 (1H, m), 7.20-7.13 (2H, m), 6.49 (1H, d, J = 2.1 Hz), 5.53 (1H, dd, J = 12.2, 2.0 Hz), 4.28 (1H, d, .1= 16.9 Hz), 3.88-3.83 (1H, m), 2.91-2.78 (3H, m), 2.59-2.48 (2H, m).
Example 110. (R)-(1-(4-fhloronhenv1)-6-((3,4,5-trifluoronhenv Dsulfon v1)-4,4a,5,6,7,8-hexah vd ro-1 Hlivrazolo13.4-glisoanino1in-43-v1)(nvridin-2-l1nnet h anon e N
NI ISO
[03711 LCMS (Method F, ES-API): RT 2.72 min, m+H = 569.1; 1H NMR (400 MHz, CDC13): 8 8.63 (1H, ddd, J = 4.7, 1.5, 1.1 Hz), 7.89-7.83 (2H, m), 7.49 ddd, J = 6.6,4.7, 1.7 Hz), 7.46-7.41 (211., m), 7.34-7.31 (211., m), 7.28 (111, s). 7.20-7.14 (211., m), 6.50(111, d, J = 2.1 Hz), 5.55 (1171, dd, J = 12.2,2.0 Hz), 4.26 (111, d, J = 16.9 Hz), 3.89-3.84 (1 m), 2.91-2.79 (3171, ni), 2.66-2.60(111, m), 2.54-2.51 (111, m).
Example 11 R. (11)-(64(3-chlora-4-fluoropheavbsulfanv1)-144-11a eropheny1)-4,4a,5,6,7,8-h.exahvtlro-11I-Dvrazolo13A-21isoci wind/ n-4a-v1)(Dvridi n-2-v1)tnethatto ne [03721 1.,CMS (Method F, ES-API): RT 2.75 min, m+11 = 567.0; 1H NMR (400 MHz, CDCI3): 6 8.61 (111, dt, J = 4.7, 1.3 Hz), 7.86- 7.79 (2H, m), 7.73(111, dd, J
= 6.7,2.3 Hz), 7.57 (111, ddd, J = 8.6, 4.3, 2.3 Hz), 7.47- 7.40(311, m), 7.27 (1H, s), 7.18 -7.13 (311, m), 6.48 (1H, d, J 2.0 Hz), 5.50 (1H, br. dd, J ¨ 12.5, 1.4 Hz), 4.24 (IH, d, J = 16.9 Hz), 3.86(111, dtd, J
8.5, 3.9, 1.9 Hz), 2.91 -2.79 (3H, m), 2.61 (1H, td, J = 11.6, 3.4 Hz), 2.55 -2.46 (1H, m).
Example 11S. (R)-34(144-fluorophenv1)-4a44-methylpieolinov1)-4a,5.7,84etrahvdro-1 H-pvrazoloi3,4-21isoonitiollin-6(4H )-v Dim Ifonvbbenzonitrile ,j--( I
4.,.., N ...NµS¨"-----'.-CN
ii-----' N", N\NJ ,..,,...) u 0.
F
LCMS (Method F, ES-API): RT 2.57 min, m+H = 554.0; 1H NMR (400 MHz, CDC13): 6 8.50 (1H, br. d, 3 = 4.9 Hz), 7.93- 7.91 (2H, m), 7.79 (1H, dt, J = 7.8, 1.3 Hz), 7.69 -7.68 (1H, m), 7.63 - 7.58 (111, m), 7.44 -7.41 (2H, m), 7.30 (1H, ddd, J = 4.9, 1.7, 0.7 Hz), 7.27 (1H, s), 7.19 -.. 7.13 (2H, m), 6.49 (1H, d, J= 2.0 Hz), 5.64(1H, dd, J =12.4, 2.0 Hz), 4.25 (1H, d, J = 16.9 Hz), 3.89 (1H, ddt, J = 8.5, 3.9, 2.0 Hz), 2.85 -2.79 (3H, m), 2.63 - 2.50 (2H, m), 2.41 (3H, s).
Example 11T. (R)-(1-(4-fluoropheny1)-641-methyl-1H-pvrazol-4-v1)sulfony1)-4,4a<5.6,7,8-hexahvdro-1H-pyrazolol3A-allSOQuinolin-4a-y1)(4-methylpyridia-2-v1)methanone ..,-i 1 ks. 0 0 0 / N N'sNTIN
ii 1 IlsN, N--"... ----.C. -,..
\
*
F
103731 LCMS (Method F, ES-API): RT 2.25 mm, m+H = 533.2; 1H NMR (400 MHz, CDC13): 6 8.49 (1H, dd, J =5.0, 0.5 Hz), 7.71 (1H, m), 7.67-7.65 (2H, m), 7.46-7.41 (211, m), 7.29-7.26(211, m), 7.19-7.13 (211, m), 6.48 (1H, d, J = 2.1 Hz), 5.47 (1H, dd, .1= 12.1, 2.1 Hz), 4.29 (11-1, d, J = 16.9 Hz), 3.91 (3H, s), 3.80-3.75 (1H, m), 2.92-2.78 (211, m), 2.68 (1H, d, J =
12.0 Hz), 2.50-2.42 (211, m), 2.40 (311, s).
.. Example I I U. (R)-(6-((3.4-difluorop henvl)sulfony1)-144-fluorophenvb-4.4a,5,6,7.8-hex a hyd ro-11-1-mrazo1013A-zlisogtuinoii it--ta-y1)(4-me th vipyridin-2-y1)m elf/ a I) on e i '-,) N
N F Y".
) [I
==== F
jc, [03741 LCMS (Method F, ES-API): RT 2.74 min, m+H = 565.2; 1H NMR (400 MHz, CDC13): 8 8.46 (1H, dd, J = 5.0, 0.5 Hz), 7.68 (1H, m), 7.50-7.40 (4H, m), 7.29-7.26 (2H, m), 7.24-7.13 (3H, m), 6.48 (1H, d, J = 2.1 Hz), 5.55 (1H, dd, J = 12.4, 2.1 Hz), 4.27 (1H, d, .1= 16.9 Hz), 3.89-3.84 (1H, m), 2.88-2.78 (3H, m), 2.62-2.56 (1H, m), 2.53-2.48 (1H, m), 2.40 (3H, s).
Example 11V. (R)-(1-(4-fluorophenv1)-6-((1-methv1-1H-imidazol-4-vbsulfonv1)-4,4a,5,6,7,8-hexahvdro-11-1-pyrazolo13.4-glisoquinoin-4a-y11(4-methylnvridin-2-yOmethanone rk-s.
0µµ p S N
!
N N
\
[03751 LCMS (Method F, ES-API): RT 2.13 min, m+H = 533.2; 1H NMR (400 MHz, CDC13): 8 8.50 (111, dd, J =4.8, 0.5 Hz), 7.71-7.70(111, m), 7.47-7.42 (311, m), 7.35 (1H, d, J
=1.4 Hz), 7.29(111, s), 7.26-7.25 (Iff, m),7.19-7.13 (211, m), 6.48 (111, d, J
= 2.1 Hz), 5.56 (1H, dd, J = 12.5, 2.1 Hz), 4.32(111, d, J = 16.9 Hz), 3.90-3.85 (1H, m), 3.72 (311, s), 2.96(111, d, J =
12.5 Hz), 2.91 (111, d, J = 16.9 Hz), 2.87-2.78 (111, m), 2.74-2.68 (1H, m), 2.49-2.44(111, in), 2.39 (3H, s).
Example I I W. (R)464(3,5-difluoropheavi)su1lon0)-1-0-flum-ophenµ11)-4,4a,5,6,7õ8-11exallydro-111-pyrazolo13.4-glisoquinolin-4a-v1)(4-meEl/v/pyridia-2-v1)methanone R
F
II/ I
103761 LCMS (Method F, ES-API): RT 2.76 min, m+1-1 = 565.0; 1H NMR (400 MHz, CDC13): 8 8.51 (1H, br. d, J= 4.9 Hz), 7.72- 7.69 (1H, m), 7.46 - 7.41 (2H, m), 7.32 - 7.27 (2H, in), 7.20- 7.13 (4H, m), 6.97 (1H, ft, J = 8.5, 2.3 Hz), 6.49 (1H, d. J = 2.1 Hz), 5.61 (1H, dd, 3=
12.3, 2.1 Hz), 4.29 (1H, d, 3= 16.9 Hz), 3.85 (1H, ddt, J = 8.4, 3.9, 2.1 Hz), 2.90 - 2.77 (3H, m), 2.63 - 2.57 (1H, m), 2.50 (1H, br. dt, J = 14.9, 2.0 Hz), 2.41 (3H, s).
Example 11X. (R)-(144-11aoronhenv1)-6-03,4,5-trifluorophenv1)sulfonv11-41,4a,5,6.7,8-hexahvdro-lH-pyrazolol3A-ulisoquinolin-4a-y1)(4-methylpyridin-2-vnmethanone , 0 0, 41:1 N

=='' 103771 LCMS (Method F, ES-API): RT 2.82 min, m+H = 583.0; 1H NMR (400 MHz, CDC13): 8 8.48 - 8.47 (1H, m), 7.69 - 7.68 (1H, m), 7.47 - 7.39 (2H, m), 7.36 -7.29 (3H, m), 7.27 (1H, s), 7.20 - 7.13 (2H, m), 6.50 (1H, d, J = 2.1 Hz), 5.58 (1H, dd, j =
12.5, 2.1 Hz), 4.26 (1H, d, J = 16.9 Hz), 3.88 (1H, dtd, j = 7.9, 4.0, 2.1 Hz), 2.91 -2.76 (3H, m), 2.72 -2.62 (1H, m), 2.56 - 2.50 (1H, m), 2.41 (3H, s).
Example 11Y. (R)-(1-(4-11uorophenv1)-64(34methvisulloml)phetry1)sulfonv1)44ax5,6,7,8-hexalivd ro-1H-pvrazolo13.4-g(isouttinolin-4a-y1)(pyridin-2-µ1)methanone N
L30 R, p N --i y s SO2Me ------------ --I
'N- -,/) '-4, F
[03781 LCMS (Method F, ES-API): RT 2.32 min, m+H = 593.2; 1H NMR (400 MHz, CDC13): 8 8.65 (1H, ddd, J = 4.7, 1.7, 0.8 Hz), 8.27-8.26 (1H, m), 8.09 (111, ddd, J = 7.9, 1.7, 1.2 Hz), 7.96 (111, ddd, J = 7.9, 1.7, 1.2 Hz), 7.87-7.80 (2H, m), 7.70-7.66(111, m), 7.48 (1H, ddd, J
= 6.6, 4.7, 1.7 Hz), 7.45-7.40 (2171, m), 7.28 (111, s), 7.19-7.13 (211, m), 6.48 (11I, d, J = 2.1 Hz), 5.56 (111, dd, I = 12.3, 2.1 171z), 4.23 (1II, d, J = 16.9 Hz), 3.91-3.87 (111, m), 3.08 (311, s), 2.91-2.79 (3H, m), 2.62-2.48 (211, m).
Exa mple 11Z. (R)-3-((1-(4-fluorophenviir4a-pieo1inoll-4a.5,7,8-te1rahvdro-1 li-ps A- af.oiol3,4-Ltlisog /se moll rs-6(4111-vhsulfonvI)benzoic add -C 7'N =-=%";
N I i 0 a...., F
103791 LCMS (Method F, ES-API): RT 2.38 min, nri-H = 559.
Example 11AA,1111)-(144-fluorovit e nv1)-6-((3-(methoxvmethyl)phenybsulfonvi)-4,4a,5,6,7.8-hexahydro- I 11-pyrazoloj3õ.4-f41 isoquinolin-4a-v1)(py ridin-2-vDmethanofte =----7'N

0a-Orvle :t Na 1 N-F
[03801 LCMS (Method F, ES-API): RT 2.54 min, m+H = 559.3; 1H NMR (400 MHz, CDC13): 8 8.67 (1H, ddd, J = 4.7, 1.4, 0.8 Hz), 7.91-7-89 (IH, m), 7.83 (11-1, dt, J = 7.5, 1.5 Hz), 7.65 (IH, tn.), 7.62-7.59 (111, m), 7.54-7.52 (111, m), 7.49-7.40(411, m), 7.29 (111, s), 7.18-7.13 (211, m), 6.46 (1171, d, J = 2.1 Hz), 5.50 (1H, dd, J = 12.4,2.1 Hz), 4.48 (211, s), 4.30(111, d, J =
16.9 Hz), 3.84-3.79 (1H, in), 3.42 (311, s), 2.91-2.77 (211, m), 2.69 (111, d, .1 = 12.1 Hz), 2.47-2.41 (2H, m).
Example 11 AB. (R)-(1-(4-11uoropheav1)-6-((4-methvl-3A-dihydro-2H-pyrido [3,2-b 1 11,41oxazin-7-y1)...mlfolq1)--lAa,5,6,7,8-hexativdro-111-.pvrazolo134-211S0tIti i 8 Olin -4 10 v1)(pvridin-2-v1)pactlianone I
rp) ,Nõ N, S" 0 N ' \\
N il i j 0 sN'''',..----"
(?, jiõ.
/
F
103811 LCMS (Method F, ES-API): RT 2.40 min, in-I-H = 587.0; 1H NMR (400 MHz, CDC13): 6 8.65(111, ddd, J = 4.7, 1.7,0.9 Hz), 8.06 (1H, d, J= 2.1 Hz), 7.89(111, dt, J = 7.8, 1.2 Hz), 7.82 (I H, td, J = 7.8, 1.8 Hi), 7.47- 7.41 (3H, m), 7.29 (1H, s), 7.19 -7.13 (2H, m), 7.04 (1H, d, J= 2.1 Hz), 6.48(111, d, J= 2.1 Hz), 5.47 (1H, dd, j = 12.2, 2.1 Hz), 4.30(111, d, J =
17.0 Hz), 4.25- 4.20 (2H, m), 3.82 - 3.77 (1H, m), 3.54- 3.52 (2H, m), 3.19 (3H, s), 2.90 (1H, d, J = 11.5 Hi), 2.85 - 2.75 (111, m), 2.70 (1H, d, J = 12.2 Hi), 2.52 - 2.45 (211, m).
Example 11AC. (R)-(1.44-111moronlienv1)-6-((2.3,4-trifluoroptienµl)sulfonyl)-4,4a,5.6,7,8-hexahydro-1E1-pvrazolo13.4-elisopuinoin-4a-v1)(pyridin-2-v1)rnethanone F

103821 LC1V1S (Method F, ES-API): RI 2.69 min, m+H = 569.0; 111 N MR (400 MHz, CDC13): 8 8.62 - 8.59 (111, m), 7.86 - 7.78(211, m), 7.49 - 7.40 (4H, m), 7.27 (11-1, s), 7.19 - 7.13 (2H, m), 6.97 - 6.91 (1H, m), 6.52 (1H, s), 5.57 (1H, dd, J = 12.8, 1.8 Hz), 4.24 (1H, d, J = 16.9 Hz), 4.02 - 3.95 (1H, m), 3.09 (1H, d, J = 12.3 Hz), 2.87- 2.80 (3H, m), 2.57 -2.49(111, m).
Example IIAD. (R)-(1-(4-fluorophenv1)-6-a6-(trifluoromethv1)pyridia-2-y1)suIfonv1)-4,4a.5,6,7,8-hexahvdro-111-pvrazolo13,4-e1isoctuinalin-4a-v1)(Pyridin-2-y1)metha none o '1\1 N CF3 'y N I I
41k 103831 LCMS (Method F, ES-API): RI 2.66 min, m-I-H = 584.2; 1H NMR (400 MHz, CDC13): 8 8.66-8.64 (111, m), 8.07-8.03 (1H, m), 7.97 (1H, d, J = 7.6 Hz), 7.85-7.79 (3H, m), 7.48-7.43 (3H, m), 7.30 (1H, s), 7.21-7.15 (2H, m), 6.54 (1H, d, J= 2.1 Hz), 5.64 (1H, dd, J=

13.2, 2.0 HZ), 4.30 (1H, d, J = 16.9 Hz), 4.06-4.01 (111, in), 3.32 (1H, d, J
= 13.0 Hz), 3.07 (1H, dd, J = 12.6, 3.5 Hz), 2.91 (111, d, J = 16.9 Hz), 2.89-2.80 (1H, m), 2.54-2.50 (1H, m).
Example 11AE. (R)-(144-fluoraphenv11-6-0-(trifluoromethvl)pyridin-2-v1)sulfativ1)-4,4a,5,6,7µ8-hexahvdro-IH-Dvrazolo13,4-aliSOQuinolin-4a-v1)(4-methvInvridin-2-y1)methanone , 0 0õ0 N C

[03841 LCMS (Method F, ES-API): RT 2.77 min, m+H = 598.2; 1H NMR (400 MHz, CDC13): 6 8.49 (1H, d, J = 4.9 Hz), 8.07-8.03 (1H, m), 7.98 (1H, d, J = 7.7 Hz), 7.82 (1H, dd, 7.7, 1.1 Hz), 7.65 (1H, s), 7.48-7.43 (2H, in), 7.29 (111, s), 7.27-7.26 (1H, m), 7.20-7.14 (2H, in), 6.53 (1H, d, J = 2.0 Hz), 5.67 (1H, dd, J = 12.8, 1.7 Hz), 4.29 (1H, d, J =
16.9 Hz), 4.06-4.02 (1H, in), 3.31 (1H, d, J = 13.0 Hz), 3.08 (lif, dd, J = 12.6, 3.5 Hz), 2.92-2.80 (211, m), 2.55-2.50 (1H, m), 2.39 (3H, s).
Example 11AF. (R)-(64(3,4-diehlorophenvbsulfonv1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-111-pyrazolof3.4-glisoquinolin-4a-y1)(Pyridia-2-y1)methanone N tam a .o 0 "s , N
N
103851 . LCVIS (Method F, ES-API): RT 2.88 min, in-1-H = 582.9; 1H NMR (400 MHz, CDC13): 6 8.61 (IEL ddd, J = 4.7. 1.7, 1.0 Hz), 7.89- 7.81 (2H, m). 7.74 (IH, dd. J = 1.7,0.5 Hz), 7.49- 7.38 (5H, m), 7.28 (1H, s), 7.20 -7.12 (2H, m), 6.50 (1H, d, J -2.0 HZ), 5.54 (1H, dd, .1= 12.4, 2.0 HZ), 4.26 (1H, d, J = 16.9 Hz), 3.88 (1H, ddt, .1= 8.4, 3.9, 2.0 Hz), 2.93 -2.79 (3H, m), 2.65 - 2.50 (211, m).
Example 11A(. (R)-(1-(4-fluoroPhenv1)-64(3-(tri 11 uoromethvi)phenvi)sulfon v1)-4,4a,5,6,7,8-hex ahvd ro-1H-pyrazolo13,4-ttlisoQ ui noli n-la-v1)(4-methylps ri di n-2-yl)methanone L. 0 0 410 N c3 \
[0386] LCMS (Method F, ES-API): RT 2.83 min, m+H = 597.0; 1H NMR (400 MHz, CDC13): 6 8.49 (1H, dd, J =4.9, 0.38 Hz), 8.00 - 7.88 (2H, m), 7.80- 7.78 (1H, m), 7.71 - 7.68 (1H, m), 7.61 (1H, t, J = 7.8 Hz), 7.46- 7.39 (2H, m), 7.29- 7.27 (2H, m), 7.19- 7.13 (2H, m), .. 6.48 (1H, d, J = 2.0 Hz), 5.61 (1H, dd, J = 12.3, 2.0 Hz), 4.27 (1H, d, J =
16.9 Hz), 3.91 -3.81 (1H, m), 2.92 - 2.78 (3H, m), 2.62 - 2.49 (2H, m), 2.40 (3H, s).
Example 11.AH. (R)-(641-ethvl-ln-pvrazol-4-0)sulfonv1)-144-fluorophenv1)-4,4a,5,6,7,8-hexah vdro-1H-pyrazolo[3.4-glisoquinolin-4a-y1)(4-methylpyridin-2-yl)m et ha II Offl e =
0 riq.N
N v IJ
.. [03871 LCMS (Method F, ES-API): RT 2.39 min, m+II = 547.0; 1H NMR (400 MHz, CDC13): 6 8.51 (1H, d, J = 4.9 Hz), 7.71 (2H, s), 7.66 (111, d, J = 0.6 Hz), 7.47 - 7.40 (211, m), 7.30 - 7.27 (211, m), 7.20 - 7.13 (2H, m), 6.48 (111, d, J = 2.0 Hz), 5.49(111, dd, J = 12.0,2.0 Hz), 4.30(111, d, J = 16.9 Hz), 4.17 (211, q, J = 7.3 Hz), 3.82 - 3.71 (III, m), 2.94 - 2.79 (211, m), 2.69 (1H, d, J = 12.0 Hz), 2.52 - 2.41 (2H, m), 2.40 (311, s), 1.50 (3II, t, J
= 7.3 Hz).
5 .. Example II Al, (R)-(64(1,5-ditnettry1-111-pvrazol-4-vOsulforev1)-1 -(4-flu orophenyI)-4.4a,5,6,7,8-hes vel ro-II-1-pyrazolol3A-glisoquinolin--la-y1)(4-methylip, vOntethan one .0 0 ,Z¨N(sNI¨

N
N-S\µ
N I j 0 [0388] LCMS (Method F, ES-API): RT 2.33 min, m+H = 547.0; 111 NMR (400 MHz, CDC13): 8 8.46 (1H, d, J = 4.9 Hz), 7.71 -7.68 (1H, m),7.61 (1H, s), 7.46 -7.41 (2H, m), 7.27 7.25 (2H, m), 7.20 - 7.13 (2H, m), 6.49 (1H, d. J = 2.0 Hz), 5.52 (1H, dd, J =
12.1, 2.0 Hz), 4.24 (111, d, J = 16.9 Hz), 3.84 - 3.80 (1H, m), 3.69 (3II, m), 2.90- 2.77 (3H, m), 2.61 - 2.48 (2H, m), 2.40 (3H, s), 2.34 (3H, s).
Example 11AJ. (R)41-(4-fluorophenv1)-64(1-methyl-1H-pyrazol-5-µ1)sulfonv1)-4,4a,5,6,7,8-hexah vdro-1H-pyrazolo[3.4-glisoquinolin-4a-y1)(4-methylpyridia-2-yl)m et ha II Offl e P
N
/11-N/Jj [03891 LCMS (Method F, ES-API): RT 2.49 min, m+11 = 533.2; 1HNMR (400 MHz, CDC13): 8 8.43 (iii, d, J = 5.0 Hz), 7.68 (1H, m), 7.47-7.41 (2H, m), 7.32(111, d, J = 2.0 Hz), 7.27-7.25 (211, m), 7.20-7.14 (211, m), 6.64 (1H, d, J = 2.0 Hz), 6.52 (111, br s), 5.59(111, dd, J =
12.4,2.2 Hz), 4.27 (1H, d, J= 16.9 Hz), 3.92-3.89 (411, m), 3.03 (iH, d, J=
12.5 Hz), 2.90-2.76 (311, m), 2.59-2.55(111, m),2.40 (314, s).
Example 11AK. (1)-(1-(4-fluorophenv11-6-((1-methyl-111-pyrazol-3-v1)sulfonv1)-4.4a,5,6,7,8-hexahl, tiro- 11-1-pyrazolo13,4-41.soquinolin-4a-y1)(4-rnetitylpµ

vOntet han one , n N \µ, ,-*".="==
N-N I
N¨N
=
[0390] LCMS (Method F, ES-API): RT 2.36 min, m+H = 533.2; 1H NMR (400 MHz, CDC13): 8 8.51 (1H, dd, J = 5.0, 0.5 Hz), 7.71 (1H, m), 7.47-7.42 (2H, m), 7.38 (1H, d, 3 = 2.2 Hz), 7.30 (1H, s), 7.27-7.25 (1H, m), 7.19-7.13 (2H, m), 6.58 (1H, d, .1= 2.2 Hz), 6.49 (1H, d, J
= 2.1 Hz), 5.55 (1H, dd, J = 12.4, 2.0 Hz), 4.33 (IH, d, J= 16.9 Hz), 3.95 (3H, s), 3.88-3.83 (1H, in), 2.92 (1H, d, J = 16.9 Hz), 2.91 (111, d. J = 12.4 Hz), 2.88-2.79(111, m), 2.68-2.61 (IH, m), 2.49-2.44 (IH, m), 2.39 (3H, s).
Example 11AL. (R)-(644-fluoro-3-methylpheavl)sulfony1)-1-(4-fluoropheriv1)-4,4a,5,6,7.8-hexahydro-111-pvrazolof 34-glisoauinolin-4a-y1)(4-niethylpliridin-2-y.1)nietha one N 0 0õ0 µs.r N
[0391] LCMS (Method F, ES-API): RT 2.90 min, m+H = 561.2; IHNMR (400 MHz, CDCI3): 8 8.50 (IH, dd, J = 5.0, 0.4 Hz), 7.69-7.68 (111, m), 7.53-7.49 (211., tn), 7.45-7.40 (211, in), 7.28-7.26(211, m), 7.19-7.13 (2H, m), 7.05-7.00 (1H, m), 6.47 (IH, d, J =
2.1 Hz), 5.52 (1.H, dd, J = 12.4, 2.3 Hz), 4.28 (I H, d, J = 16.9 Hz), 3.86-3.81 (1H, m), 2.89-2.78 (2H, m), 2.74 (1H, d, J = 12.3 Hz), 2.54-2.46 (21-1, m), 2.40 (311, s), 2.28 (3II, d, J = 1.7 Hz).
Example I I AM. (R)-(144-fluoropheny1)-6-((4-metliv1-3,4-dilivdro-2H-pyrido13,2-bl11,41oxazia-7-v1)sulfotiv1)-1..4a,5,6,7,8-hexahvdro-1 fl-pyrazo1o13,4-glisoaninolin-4a-v1)(4-inethylpvridiri-2-vlitriethanone ---JT

-'N ' 9P
z.õ....,..,.. ,-,N-aij Iii II
! I
\ it F
[03921 LCMS (Method F, ES-API): RT 2.58 min, m+H = 601.3; 111 NMR (400 MHz, CDC13): 8 8.49 (1H, d, J = 4.9 Hz), 8.06 (1H, d, J = 2.0 Hz), 7.71 (1H, m), 7.46-7.41 (2H, m), 7.28 (1H, s), 7.25 (1H, m), 7.19-7.12 (2H, m), 7.04 (1H, d, J = 2.0 Hz), 6.46 (1H, d, J = 2.1 Hz), 5.50 (111, dd, .1 = 12.3, 2.1 Iiz), 4.29 (1H, d, J = 16.9 Hz), 4.22-4.20 (211, m), 3.80-3.76 (1[1, m), 3.54-3.52 (2H, m), 3.19 (311, s), 2.88 (III, d, J = 16.9 Hz), 2.84-2.75 (111, m), 2.69 (ITI, d, J =
12.3 Hz), 2.52-2.44 (211, m), 2.40 (3H, s).
Example 11AN. (R)-(6-(2,3-dihydrobencofuran-5-v1)sulfonyl)-1-(441norophenyl)-4,4a.5.6.7.8-hexahvdro-1H-pvtazolo13,41-21isooninolin-4a-v1)(4-methvItoridin-2-vl)methanone .....-* , -...N I 0 s 0 µs*
N,/ I 0 N' 110 *
F
[0393] 11,CMS (Method F, ES-API): RT 2.73 min, m+II = 571.2; tH NMR (400 MHz, CDC13): 8 8.47 (1H, d, J = 4.9 Hz), 7.71-7.70 (1H, m), 7.49-7.41 (4H, m), 7.27-7.26 (2H, m), 7.19-7.13 (2H, m), 6.78-6.75 (I TI, m), 6.47(1!], d, J = 2.0 Hz), 5.51 (111, dd, .1= 12.3, 2.1 Flz), 4.67-4.63 (2H, m), 4.30 (1H, d, Jar: 16.9 Hz), 3.84-3.79 (1H, m), 3.24-3.20 (2H, m), 2.90-2.78 (211, m), 2.67 (1H, d, J = 12.3 Hz), 2.48-2.40 (511, m).
Example 11A0. (R)-5-(044-fluorophenv1)-42-(4-methvIpieolinovn¨la,5,7,8-tetrahvdro-1H-pvrazolol3,4-fdisoo ui nolin-6(411)-vbsu lion vI )-1-niet hylindolin-2-one 0 0õ0 N.µSi [03941 LCMS (Method F, ES-API): RT 2.44 min, m+H = 598.3; 1H NMR (400 MHz, CDC13): 8 8.44 (1H, d, J = 4.9 Hz), 7.70-7.68 (2H, m), 7.52 (1H, d, J = 0.9 Hz), 7.45-7.40 (2H, m), 7.26 (1H, s), 7.24-7.23 (1H, m), 7.19-7.13 (2H, m), 6.82 (1H, d, J = 8.3 Hz), 6.47 (1H, d, J =
2.0 Hz), 5.53 (1H, dd, J = 12.3, 2.0 Hz), 4.25 (1H, d, J = 16.9 Hz), 3.88-3.84 (1H, m), 3.53, 3.47 (211, All system., J = 22.4 Hz), 3.22 (311, s), 2.89-2.79 (211, m), 2.72 (Hi, d, J = 12.3 Hz), 2.53-2.46 (2H, m), 2.39 (3H, s).
Example 11AP. (R)-(1-01-fluorophenyl)-64(3-(methvIsulfonyl)phenybsulfonv1)-4,4a.5,6,7,8-hex ahvd ro-1H-pyrazolof 3.4-g1 isoquinolin-4a-yI)(4-methylpyridi I )me thanone , NS SO2Me [03951 I,CMS (Method F, ES-API): RT 2.52 min, m+H = 607.2; 1H NMR (400 MHz, CDC13): 8 8.49 (111, d, J = 4.9 Hz), 8.26-8.25 (111, m), 8.09 (111, ddd, J =
7.9, 1.7, 1.2 Hz), 7.97 (111, ddd, J = 7.9, 1.7, 1.2 Hz), 7.69-7.66 (111, m), 7.45-7.40 (211, m), 7.29-7.26 (211, m), 7.19-7.13 (211, n1),6.48 (11-1, d, J= 2.1 Hz), 5.60(111, dd, J =12.3, 2.1 Hz), 4.23 (111, d, J= 16.9 Hz), 3.92-3.87 (1H, m), 3.08 (3H, s), 2.88-2.79(311, m), 2.63-2.49 (211, m). 2.40 (311, s).
Example 11AQ. (R)-(6-((1.3-dimetliyi- I 1i-ovrazol-4-s1)sti11on1-(4-tillorophenv1)-4,4a,5,6,7,8-hexahydro-1H-pvrazolof3.4-21isoquinoÃin¨la-vi1(A-Inclbylo ridi n-vOmeth anon c i 70 ,-"N. .0 0,, , N S\b Ni =
[03961 LCMS (Method F, ES-API): RT 2.33 min, m+H = 547.0; 1H NMR (400 MHz, CDC13): 8 8.44 (1H, d, J =4.9 Hz), 7.71 - 7.69 (1H, m), 7.59 (1H, m),7.46 -7.41 (2H, m), 7.28-7.26 (2H, m), 7.20 - 7.13 (2H, m), 6.50 (1H, d, J = 2.0 Hz), 5.49 (1H, dd, J =
12.1, 2.0 Hz), 4.28 (1H, d, J = 16.9 Hz), 3.85 - 3.76 (4H, m), 2.92 - 2.78 (3H, m), 2.63 - 2.48 (2H, m), 2.40 (3H, s), 2.27 (3H, s).
Example 11AR., (R)4642,3-dihydrobertzolbll1.41d1ox1n-6-vbsulfonvl)-1-(4-fluorophenv1)-4,4a.5,6,7.8-hexahvdro-1H-pyrazolo13,4-tzlisoquinalin-4a-vl)(4-methylpyridin-2-v1)methanone 0 0µ ) ;SN 0 N N
, 1 !
N
[03971 LCMS (Method F, ES-API): RT 2.60 min, m+H = 587.0; 1HNMR (400 MHz, CDC13): 8 8.50(111, d, J = 4.9 Hz), 7.71 (111, s), 7.45 -7.41 (2H, m), 7.28 -7.26 (2H, in), 7.22 -7.13 (411, m), 6.89 (1H, d, J= 8.5 Hz), 6.46(111, d, J = 1.9 Hz), 5.49 (111, dd, J = 12.2, 1.9 Hz), 4.31 -4.25 (511, m), 3.81 -3.73 (IH, m), 2.92 - 2.77 (211, m), 2.68 (1FT, d, J
= 12.2 Hz), 2.50 -2.39 (511, m).
Lsanipie 11AS. (R)-(64(3-fluoro-4-(trilluoremetliel)phenvl)su1fonv1)-1-(4-fluoronheny1)-4,4a,5,6,7.8-hexahvdro-111-pyrazolo1 isoq It i n oli rfr4a-v1)(4-methylpsi ridi n-2-vl )tnethanone .---'1'--, '-'=... -,-,,,0 0 0 N r." =,%,.
N
NF
N / _ :
) I

r_---k, Y
F
[03981 LCMS (Method F, ES-API): RT 3.03 min, m+H = 615.2; 1H NMR (400 MHz, CDC13): 6 8.47 (1H, dd, J =4.9, 0.3 Hz), 7.69-7.65 (2H, m), 7.58-7.56 (1H, m), 7.48 (1H, br d, J
= 9.4 Hz), 7.45-7.40 (2H, m), 7.28 (1H, ddd, J = 4.9, 1.6, 0.7 Hz), 7.26 (1H, s), 7.19-7.13 (2H, m), 6.49 (IH, d, J = 2.0 Hz), 5.64 (1H, dd, J = 12.5, 2.0 Hz), 4.23 (1H, d, .1= 16.9 Hz), 3.92-3.88 (1H, m), 2.91-2.80 (3H, m).2.69-2.63 (1H, m), 2.55-2.50 (1H, m), 2.39 (3H, s).
Example HAT. (11)-(64(3-fluoro-4-(trifluaromeltvl)ahenyl)sulfonvI)444-fluorophenv1)-4Aa,5,6,7.8-hexahvdro-lH-pyrazolo13,4-glisoqui a olin-4a-vl)(py ridin-2-v 1)m etha n on e ..'"
..--- , I
0, /0 N
/7- '''''N "µ.4.."7"=-='-". F
N, 11 j ll ...,.
N - '-'-'-. '''''CF3 F
[0399l LCMS (Method F, ES-API): RI 2.93 min, in-1-H = 601.2; 111 NMR (400 MHz, CDC13): 6 8.64 (1H, ddd, J = 4.9, 1.5, 1.1 Hz), 7.87-7.81 (2H, m), 7.71-7.67 (1H, m), 7.57 (1H, br d, J = 8.2 Hz), 7.51-7.47 (2H, m), 7.45-7.40 (2H, m), 7.28 (IH, s), 7.19-7.13 (2H, m), 6.50 (1H, d, J = 2.0 Hz), 5.59(111, dd, J - 12.4, 2.0 Hz), 4.25 (1H, d, j = 16.9 Hz), 3.92-3.87 (1H, m), 2.91-2.80 (3H, m), 2.67-2.61 (1H, m), 2.55-2.51 (IH, in).
IS .. Example 11 AU. (R)-3-((48-(4-ethylpieolinov1)-144-fluorophenv1)-48.5,7,8-tet ra WO ro-11-1-pyraz01013.4-21isoa 'limn n-6(4M-vbsulfonvl)benzonitrile I, -Li 0 0 NN CN
[0400] I.,CMS (Method F, ES-API): RT 2.79 min, m+H = 568.2; 1H NMR (400 MHz, CDC13): 8 8.53 (1H, dd, J =4.9, 0.5 Hz), 7.95 (1H, m), 7.91 (1H, ddd, J = 7.9, 1.9, 1.2 Hz), 7.78 (1H, ddd, J =: 7.9, 1.2, 0.3 Hz), 7.71-7.70 (1H, m), 7.59 (1H, dt, J = 7.9, 0.5 Hz), 7.45-7.40 (2H, m),7.33-7.32 (1H, m), 7.27 (iH, s), 7.19-7.13 (2H, m), 6.49 (1H, d, J = 2.0 Hz), 5.64 (1H, dd, J
12.3, 2.0 Hz), 4.25 (1H, d, J = 16.9 Hz), 3.91-3.86 (1H, m), 2.88-2.80 (3H, m), 2.71 (2H, q, J
7.7 Hz), 2.63-2.50 (2H, m), 1.27 (3H., t, J = 7.7 Hz).
Example 11AV, (R)-(4-etlivluvridin-2-1,1)(14.1-flutickpi3hvel v1mwridin-2-vbsulfonvi)-4.42,5,6,7,8-hmall v(h-o-11-1-ovrazolo13,4-I 0 Ldisoottioo1ut-4a-1)methanone 'S' N CF3 [0401] LCMS (Method F, ES-API): RT 2.93 min, m+H = 612.2; 1H NMR (400 MHz, CDC13): 8 8.51 (III, dd, J =4.9, 0.5 Hz), 8.06-8.02 (111, m), 7.99-7.97 (111, m), 7.81 (111, dd, J =
7.9, 1.2 Hz), 7.67 (111, m), 7.48-7.43 (211, m), 7.29 (111, s), 7.28-7.27(111, m), 7.20-7.14 (211, in), 6.53 (111, d, J = 2.0 Hz), 5.67 (111, dd, j = 12.3, 2.0 Hz), 4.28 (111, d, J = 16.9 Hz), 4.06-4.02 (111., m), 3.31 (1H, d, J = 13.0 Hz), 3.12-3.05 (1.H, m), 2.91-2.81 (211, m), 2.69 (211, q, J = 7.7 Hz), 2.54-2.50 (111, m), 1.26 (3H, t, J = 7.7 Hz).

Example 11AW. (R)-3-01-(4-f1uorophen 1-1)-4a44-methy1picolinov1)-4a,5.7,8-tetrakydro-1H-pyrazolo13,4-allsofininolin-6(4H)-v1isulfonv1)benzalc acid ci 0 0, 1411 OH
Ns 10 N 0 [04021 LCMS (Method F, ES-API): RT 2.47 min, m+H = 573.0; 1H NMR (400 MHz, CDC13): 8 8.55 (1H, d, J = 5.0 Hz), 8.17 (1H, dt, J = 7.9, 1.2 Hz), 8.07 (1H, t, J = 1.7 Hz), 7.88 (1H, dt, J = 8.2, 1.2 Hz), 7.70 (1H, t, J = 7.9 Hz), 7.60 (1H, m), 7.51-7.45 (3H, m), 7.41-7.35 (3H, m), 6.63 (1H, s), 5.39 (1H, d, J = 12.2 Hz), 4.13 (111. d, J = 17.0 Hz), 3.77-3.71 (1H, m), 2.92-2.84 (2H, m), 2.69-2.44 (3H, in), 2.38 (3H, s).
FN.:trunk 11AX. (R)-(643,5-dimethylisexazol-4-vi)sillfony1)-1-(4-flaoroplienv1)-4,4a.5,6,7,8-h ex a hyd ro-1 H-pvrazolo iso9 n-4a-xl)(4- methyl nvridia-2-yl)meth an on c 0 0õ0 NrµS/X(,o N
[04031 LCMS (Method F, ES-API): RI 2.79 min, m+11 = 548.2; 1H NMR (400 MHz, CDC13): 6 8.38 (iH, d, J = 4.9 Hz), 7.65-7.64 (111, m), 7.46-7.41 (211, m), 7.28-7.26(111, m), 7.25 (1H, s), 7.20-7.14 (2H, m), 6.52 (I H, s), 5.49 (1H, dd, J = 12.6,2.1 Hz), 4.24 (lti, d, J =
16.9 Hz), 3.95-3.92 (11-1, m), 3.04 (1H, d, J = 12.6 Hz), 2.90-2.79 (3H, m), 2.62-2.55 (iii, m), 2.53 (3H, s), 2.39 (3H, s), 2.21 (3H, s).

Example 11AY. (R)-(6((I-ethy1-1 H-pyrazol-4-vbsullonv1)-1 -(4-Iluorophenv1)-4,4a,5,6,7,8-hex a hydro-TH-Dvrazolo13.4-elisoquinolin-4a-171)(Dvridin-2-y1 )methanmie N I 0 0, LINIµN-/
Ni N
[04041 I,CMS (Method F, ES-API): RT 2.28 min, m+H = 533.0; 1H NMR (400 MHz, CDC13): 8 8.66 ddd, J = 4.7, 1.7, 0.9 Hz), 7.92 - 7.87 (1T-1, m), 7.83 (1H, td, .1= 7.5, 1.7 Hz), 7.71 (lH, s), 7.66 (1H, s), 7.48 - 7.41 (3H, m), 7.30 (111, s), 7.21 - 7.13 (2H, m), 6.49(11,, d, J =
2.0 Hz), 5.46 (1H, dd, J = 12.0, 2.0 Hz), 4.31 (1H, d, J= 16.9 Hz), 4.17 (2H, q, J= 7.3 Hz), 3.80 - 3.75 (1H, m), 2.95 - 2.77 (2H, m), 2.69 (1H, d, J = 12.0 Hz), 2.52 - 2.40 (2H, m), 1.50 (3H, t, J
= 7.3 Hz).
Example 11AZ. (R)-(1-Dhenv1-6-03-(trifluoromethypphenvl)sulfo II v1)-4,4a.5,6.7,8-11exalivdro-IH-rivrazolo13.4-elisocminolin-4a-v1)(nvridin-2-v1)methartmte , N

[04051 LCMS (Method F, ES-API): RT 2.72 min, m+H = 565.0; 1H NMR (400 MHz, CDC13): 8 8.64 (1H, ddd, J = 4.7, 1.7, 0.9 Hz), 7.94 - 7.78 (5H, m), 7.61 (1H, t, J = 7.8 Hz), 7.50 -7.45 (5H, m), 7.39 - 7.33 (1H, m), 7.29 (iH, s), 6.56 (11-1, d, J = 2.1 Hz), 5.56 (1H, dd, J = 12.3, 2.1 Hz), 4.25 (1H, d, J= 16.9 Hz), 3.90- 3.84 (1H, m), 2.92- 2.78 (3H, m), 2.58 - 2.48 (2H, m).
Example. JIBA. (R)-(64(1.3-dimethvI4H-Dvrazol-5-v1)su1fonv1)-1-(4-f1uorophenva:
4,4a.5.6.7.8-14.xahvdro-111-rovrazo1013.4-glisoQuinoiin-4a-v1)(4-trwthviDs ridi viffile th anone i '75 N CZµsµ,1,1 N\M
/ I 7 '0 N
[04061 LCMS (Method F, ES-API): RT 2.54 min, m+H = 547.1; 1H NMR (400 MHz, CDC13): 8 8.42 (1H, d, J = 4.9 Hz), 7.70 - 7.68 (1H, m),7.48 - 7.41 (211, m), 7.26 - 7.24 (2H, m), 7.21 - 7.14 (211, m), 6.52(111, d, J= 1.9 Hz), 6.40(1H, d, J= 0.39 Hz), 5.58 (1H, dd, J = 12.5, 1.9 Hz), 4.28 (1H, d, J = 16.8 Hz), 3.94 - 3.87 (III, m), 3.84 (3171, s), 3,02 (1H, d, J = 12.5 Hz), 2.91 - 2.75 (311, m), 2.60 - 2.53 (1H, m), 2.39 (3H, s), 2.17 (3H, s).
Example 11BB. (R)-(1-(4-fluoropheny1)-64(2-(trifluoromethyl)pyridin-4-v1)sulfonv1)-4,4a,5,6,7.8-hexahvdro-lH-pyrazolo13,4-ulisoquinolia-4a-v1)(4-methylpyridin-2-v1)methanone , 0 oõo N
N
[04071 LCMS (Method F, ES-API): RT 2.99 min, m+H = 598.2; 1H NMR (400 MHz, CDC13): 8 8.83 (111, d, J = 5.0 Hz), 8.46 (III, dd, J = 5.0, 0.4 Hz), 7.86(111, m), 7.71 (111, dd, = 5.0, 1.3 Hz), 7.63-7.62 (1H, m), 7.45-7.40(211, m), 7.29-7.26(211, m), 7.19-7.13(211, m), 6.50 (III, d, J = 2.0 Hz), 5.64(111, dd, J = 12.6, 2.0 Hz), 4.20 (1H, d, J = 16.9 Hz), 3.95-3.90 (111, m), 2.97 (Iii, d, J= 12.6 Hz), 2.88-2.80 (211, m), 2.77-2.70(111, m), 2.57-2.53 (111, m), 2.39 (3H, s).
Lsanipie 11BC. (RH1-(4-11uorookenv1)-6-(t4-( tril1tioromethvi)pyridin-2-v1)sullonv1)--1,4a,5,6,7.8-hexahydro-1H-pyrazolo[3,4-glisoqUinolin-,1a-vl)(.4-inethylpsiridin-2-vlitnethanone CF
/7-7 1=1- 'Tr---"`=-='' 3 N ,I;
[04081 LCMS (Method F, ES-API): RT 3.13 min, m+H = 598.2; 1H NMR (400 MHz, CDC13): 6 8.82 (1H, d, J = 4.9 Hz), 8.50 (LH, dd, J = 4.9, 0.9 Hz), 7.98 (1H, m), 7.65-7.62 (2H, m), 7.47-7.42 (2H, m), 7.27-7.26 (2H, m), 7.20-7.14 (2H, m), 6.51 (1H, d, J =
2.0 Hz), 5.78 (1H, dd, J= 12.9, 2.0 Hz), 4.25 (1H, d, J= 16.9 Hz), 4.07-4.02 (1H, m), 3.28(111, d, J = 12.9 Hz), 3.02-2.96 (1H, m), 2.92-2.83 (2H, m), 2.54-2.49 (1H, m), 2.38 (3H, s).
Example 11BD. (R)-(1-(4-fluorophenv1)-6-((5-methyl-1H-pyrazol-4-yDsulfonv1)-4.48,5,6,7,8-hexahvdro-1H-pyrazolo13.4-glisoquinolin-4a-y1)(4-methylpyridin-2-y1)methanone N I 0 oõo .. [04091 11,CMS (Method F, ES-API): RT 2.54 min, m+FI = 533.2; 1HNMR (400 MHz, CDC13): 6 8.45 (iii, d, J = 4.9 Hz), 7.74 (I H, s), 7.71-7.70 (1H, m), 7.46-7.41 (2H, m), 7.28 (1H, s) 7.26-7.25 (211, m), 7.20-7.14 (211, m), 6.49 (111, d, J = 2.0 Hz), 5.52 (1.H, dd, J = 12.0, 2.0 Hz), 4.27 (111, d, J = 16.9 Hz), 3.84-3.81 (111, n1), 2.91-2.78 (311, m), 2.60-2.49 (211, m), 2.39 (611, s).
Example 11BE. (R)-(1-(4-111uoropiten vi)-6-4(2-(trifluorometivvi)pyridin-4-vi)sulfonyt)-4,4a,5,6,7,8-hex allvd ro-11H-ovrazolo13,4-glisoquitiolin--ta-yl)(pyridin-2-ybotetita none --0, 'NC) 9,P
--, F

/7"I
I I I
sN--'\,--'' `../' .N.1r-N
/
\--- /
F
104101 LCMS (Method F, ES-API): RI 3.07 min, m+H = 584.2; 1H NMR (400 MHz, CDC13): 8 8.86 (1H, d, J = 5.0 Hz), 8.64 (1H, dt, J = 5.0, 1.6 Hz), 7.87(1H, m), 7.85-7.83 (2H, m), 7.72 (1H, dd, j = 5.0, 1.3 Hz), 7.52-7.46 (1H, m), 7.45-7.40 (2H, m), 7.28 (1H, s), 7.20-7.14 (2H, m), 6.51 (1H, d, J = 2.0 Hz), 5.61 (111, dd, J = 12.5, 2.1 Hz), 4.22 (1H, d, J = 16.9 Hz), 3.94-3.90 (1H, m), 2.94 (1H, d, J = 12.5 Hz), 2.90-2.80 (2H, m), 2.73-2.66 (1H, m), 2.57-2.53 (1H, m).
Example 11BF. (R)-(6-((4-ehloro-3-(trifluoromethyBahen vi )s ail ny1)-1-(4-fluoropheny1)-4,4a,5,6.7.8-hexahydro- 1 H-nyrazolof 3.4a1 esoquinolin-4a-y1)(pyridin-2711)methanone 4-------,11 =-=r\r-%t 0 00 ,r, ... N..Ni.i.,...õ, .CF3 N, 11 j' N -''' ---.1) 1.;.. /
F
[0411] I.,CMS (Method F, ES-API): RI 3.39 min, m+H 616.8; IFI NMR (400 MHz, CDC13):
6 8.60-8.58 (1H, m), 7.97 (1H, d, J = 2.1 Hz), 7.85-7.80 (2H, m), 7.76(111, dd, J = 8.4, 2.1 Hz), 7.52 (1H, d, J - 8.5 Hz), 7.48-7.40(3K, m), 7.27(11-1, m), 7.19-7.13 (21-1, in), 6.50(1K, d, J - 2.1 Hz), 5.54 (1H, dd, J ... 12.6,2.0 Hz), 4.22 (1H, d, J = 16.9 Hz), 3.93-3.88 (1H, m), 2.90-2.80 (3H, m), 2.68-2.61 (11-I, m), 2.56-2.51 (1H, m).
Example 11BG. (R)-(64(3-chloro-4-metliviplaenvI)sulfonv1)-1-(4-fluorophenv1)-4,4a,5,6,7,8-hexahvdro-1H-ovraio1o13.4-ellsoa1inolia-4a-v1)(m ritli u-2--µ 1)tiw I It a M?8 e -1-N, li 0 N
(--m---,..õ... ,:s\--------ci b I
' N '''' ) Na N

F
104121 LCMS (Method F, ES-API): RT 2.81 min, m+H 563.0; 1H NMR (400 MHz, CDC13): 6 8.64 (1H, ddd, J - 4.7, 1.8, 0.9 Hz), 7.91 -7.87 (1H, m), 7.83 (1H, td, J =
7.4, 1.7 Hz), 7.64 (1H, d, .1- = 1.8 Hz), 7.50- 7.40 (4H, m), 7.31 (1H, 0, 7.29 (111, 0, 7.20- 7.12 (2H, m), 6.48 (1H, d, J
.. =2.1 Hz), 5.52 (1H, dd, J - 12.2, 2.1 Hz), 4.29 (1H, d, J= 16.9 Hz), 3.86-3.82 (1H, m), 2.92 -2.70 (3H, m), 2.54 - 2.47 (2H, m), 2.40 (3H, s).
ENample 111311. (R)-(6-((3,4-ilifluoronhelovIlsulfonyl).-144-fluorophenv1)-4i4a.546,7õ8-hexahvdro-111-nvrazolo13.4-21isoonitiolin-4a-v1)(2-(nvrrolidin- 11-v1)nvridin-4-v)inethanone I ............................... 1 cN) Na...1 =-- I 0 0õ0 N:e tigiti.h F
INV I
'lkl Will F
*
F
104131 LCMS (Method F, ES-API): RT 2.11 min, m+H = 619.9; 1H NMR (400 MHz, CDC13): 6 8.14 (1H, d, j = 5.0 Hz), 7.69-7.59 (2H, m), 7.46 (1H, s), 7.40-7.35 (3H, m), 7.21-7.15 (2H, m), 6.50 (1H, dd, J - 5.2, 1.2 Hz), 6.39 (2H. d, J = 14.0 Hz), 4.56 (1H, dd, J = 11.4, 1.6 Hz), 3.88-3.87 (1H, m), 3.36-3.30 (5H, m), 2.70 (1H, d, J = 16.9 Hz), 2.48-2.36 (4H, m), 1.97-1.89 (4H, m).
Example 11131. (R)-(1-(4-11tAoronheal,11-64(1- methvI-111-Dvrazol-3-v1)su IfonvI)-4,4a,5,6,7,8-hexahvd ro- I 11-pµ razolo13.4-21isoquittan--4a-v1)(4-(tritinoromethµ11pµ rid in -2-vl)methanone I

\Ng' ,/
N N-N
[04141 I..CMS (Method F, ES-API): RT 2.42 min, m+II = 587.0; III NMR (400 MHz, CDC13): 8 8.89 (111, d, J = 5.0 Hz), 8.14 (111, m), 7.70-7.68 (111, m), 7.47-7.42 (211, m), 7.39 (1H, d, J = 2.3 Hz), 7.31 (III, s), 7.21-7.15 (211, m), 6.57 (1H, d, J = 2.2 Hz), 6.52 (lii, d, .1= 2.1 Hz), 5.56 (iii. dd, J = 12.6,2.1 Hz), 4.24(111, d, J = 16.9 Hz), 3.96 (311, s), 3.89-3.85 (1H, m), 2.96 (111, d, J= 16.9 Hz), 2.93 (1H, d, J =12.4 Hz), 2.88-2.79(111, m), 2.68-2.61 (111, m), 2.51-2.47 (1H, m).
Examnle 11113. (R)-(1-(41-f1uorophen,,1)-6-((1-methyl-111-13,, rato1-3-v1)su1fonv1)-44a,5,6,7,8-hexahydro-1H-ovrazo1op ino1io-4a-v1)(Dvrid I it anone N \Si/" = (sky N I
N-N
41Ik 104151 LCMS (Method F, ES-API): RT 2.15 min, m+H = 519.0; 1H NMR (400 MHz, CDC13): S 8.67 (1H, ddd, - 4.7, 1.7, 0.9 Hz), 7.91-7.88 (1H, m), 7.85-7.81 (1H, m), 7.48-7.42 (3H, m), 7.38 (1H, d, J = 2.2 Hz), 7.31 (1H, s), 7.20-7.14 (2H, m), 6.58 (1H, d, J = 2.2 Hz), 6.50 (1H, d, S = 2.1 Hz), 5.54(111, dd, J = 12.5, 2.0 Hz), 4.34 (1H, d, J = 16.9 Hz), 3.95 (3H, s), 3.88-3.84 (1H, m), 2.94 (1H, d, 5= 16.9 Hz), 2.91 (1H, d, J = 12.4 Hz), 2.88-2.79 (1H, m), 2.67-2.60 (1H, m), 2.50-2.45 (1H, m).

Example 11BK. (R)-(144-fluorophenv1)-6-05-nietliv1-1H-pyrazol-4-yBsulfonyl)-4,4a.5,6.7,8-hexahydro-1H-pyrazolo13,4-glisoquinolin-4a-y1)(4-(trifluoromethyl)pyridin-2-vOmethanone cF3 .-- 1 , . 0 iskNiL N
i.,..,,.....) 11:1, /, iH
).... /
F
[04161 LCMS (Method F, ES-API): RT 2.36 min, m+11 = 587.0; 1H NMR (400 MHz, CDC13): 6 8.83 (iii, d, J = 4.9 Hz), 8.14-8.13 (III, m), 7.73 (1H, s), 7.68 (lH, dd, J = 4.9, 1.1 112), 7.46-7.41 (211, m), 7.29 (11i, s), 7.20-7.14 (211, m), 6.51 (iH, d, J =
2.1 Hz), 5.45 (111, dd, J
¨ 12.3, 2.0 Hz), 4.19 (111, d, J ¨ 16.9 Hz), 3.85-3.80(111, iii), 2.93 (111, d, J ¨ 16.9 Hz), 2.86-2.78 (211, m), 2.59-2.50 (211, m), 2.38 (311, s).
Eva nip le 11 Ill,. (R)-341144-fluOronhenvE)-4a-(44trilluorometh V )picolinov0-4a,5,7,8-ictrabv(iro-11i-r)yrazo1o1344-g1iso(ui n Oki-h( 411 )-vE)siiittons 1)1)efliolli tri le ...----ks I
s /,,,,r,,,_,.. -f\l`'' (14) N....S 401 CN
Ns I 1 N.N.,''' i n )_...., F
104171 LCMS (Method F, ES-API): RT 2.68 min, m+H = 608.0; 111 .NMR (400 MHz, CDC13): 6 8.90 (1H, d, j ¨ 5.0 Hz), 8.13 (1H, in), 7.98 (1H, m), 7.91-7.89 (1H, m), 7.84-7.81 (1H, m), 7.74 (111, dd, j = 5.0, 0.9 Hz), 7.65-7.61 (111, m), 7.45-7.40 (211, m), 7.29 (1H, s), 7.20-7.14 (2H, m),6.51 (111, d, J = 2.0 Hz), 5.53(111, dd, J =12.3, 2.0 Hz), 4.18(111, d, J= 16.9 Hz), 3.91-3.87 (1H, m), 2.90 (1H, d, j = 16.9 Hz), 2.88-2.77 (2H, m), 2.58-2.51 (2H, m).

Example 1IBM. (M-(1-(4-fluoronhenV1)-6-((1-methyl-1H-Dvrazol-5-171)sulfony1)-3,4a.5,6.7,8-hexahydro-1H-Dyrazo1o13,4-g1isoquinolin-4a-y1)(4-(trifluoromethyllovridin-2-v1)methanone NI N,110f.\, ./ /N -N
[04181 L.CMS (Method F, ES-API): RT 2.55 min, m+11 = 587.0; 1H NMR (400 MHz, CDC13): 6 8.81 (111, d, J = 4.9 Hz), 8.12 (1E1, m), 7.70-7.69 (1E1, m), 7.47-7.41 (21:1, m), 7.35 (1H, d, J = 2.1 Hz), 7.28 (1H, s), 7.21-7.15 (211, m), 6.62 (1H, d, J = 2.1 Hz), 6.54(111, d, J = 2.0 Hz), 5.50(111, dd, J - 12.4,2.0 Hz), 4.18 (1H, d, J - 16.9 Hz.), 3.95 (311, s), 3.94-3.90(111, In), 3.02 (Iii, d, J= 12.6 Hz), 2.92(111, d, J =16.9 Hz), 2.86-2.74(211, m), 2.60-2.55 (IH, in).
Example 11BN. (14464(1,5-dimeiliv1-111-pvrazol-4-v1)sulfonyl)-144-fluoroohenv1)-4.47,8-1¶:Nalivdro-11-1-pyrazoloi 3,-1-1,T,Eisoquinonn-4a-v11(4-(trilluorometb vhnvrid in-2-vi)tnethan on i I
110419] LCMS (Method F, ES-API): RT 2.44 min, ml-H - 601.2; 1H NMR (400 MHz, CDC13): 8 8.84 (1H, d, J = 4.9 Hz), 8.13 (1H, br s), 7.69 (1H, dd, = 4.9, 1.0 Hz), 7.61 (1H, s), 7.47-7.41 (2H, m), 7.28 (111, s), 7.20-7.14(2H, m), 6.51 (1H, d, J = 2.0 Hi), 5.46 (1H, dd, J =

12.3, 1.9 Hz), 4.16 (1H, d, J= 16.9 Hz), 3.85-3.79 (1H, m), 3.71 (3H, s), 2.92 (1H, d, J 16.9 Hz), 2.87-2.76 (2H, m), 2.58-2.50 (2H, m), 2.34 (3H, s).
Example 11130. (R)-(641H-pyrazo1-4-11)sulfonv1)-1-(4-fluoronheav1)-4.4a,5,6.7,8-hexall µ11ro-11-1-pyrazolof3.4-1,11isoquilielin-4a-s-1)(4-(tri11aorometla%
f)1p, yl)methaamte CFNH
`===='-,HN 0 N
[04201 I,CMS (Method F, ES-API): RT 2.28 min, m+H = 573.2; 1.1-INMR (400 MHz, CDC13): 6 11.0 (1H, br s), 8.86 (1H, d., J = 4.9 Hz), 8.15 (1H, m), 7.83 (2H, s), 7.71-7.69 (1H, in), 7.46-7.41 (2H, m), 7.31 (1H, s), 7.20-7.14 (2H, m), 6.50 d, J= 2.0 Hz), 5.44 (1H, dd, J
= 12.1, 2.0 Hz), 4.20 (1.H., d, J = 16.9 Hz), 3.82-3.78 (1H, m), 2.92 (1H, d, J = 16.9 Hz), 2.87-2.78 (1H, m), 2.61 (1H, (.1, = 12.2 Hz), 2.52-2.40(2H, m).
Example 11 BP. (R)- 14441 orophenv1)-64( 1 -methyl-3-(trifluorometh vb-1.11-pvrazol-4-vbsulfon y1)-4,4a,5,6,7.8-1/ exa h yr1 ro-111-avrazolo13,4-disoqui nolin-4a-v1)(pyridi n-2-vt)metha n one N C N
N
N
[0421] I,CMS (Method F, ES-API): RT 2.47 min, m+F1 587.0; 1H INIMR (400 MHz, CDC13): 6 8.61 (1H, ddd, J = 4.8, 1.7, 0.9 Hz), 7.90 - 7.80 (2H, m), 7.74 (1H, s), 7.48 -7.42 (3H, rn), 7.28 (1H, s), 7.21 -7.14 (2H, m), 6.51 (1H, d, .1= 2.0 Hz), 5.50 (1H, dd, J = 12.6, 2.0 Hz), 4.26 (1H, d, J = 16.8 Hz), 3.92 (3H, s), 3.89- 3.85 (1H, m), 2.98 (111, d, J = 12.6 Hz), 2.90 (1H, d, J = 16.8 Hz), 2.86 - 2.68 (2H, m), 2.56 - 2.46 (1H, m).
ExaninIe 11130. (R)-(11-(4-11norophenv1)-6-((3,41,5-trifluorophenv1)sulfon 1)-4,411,5,6,7,8-itexalivtiro-1H-pvrazollo13A-g1isoquino1in-4a-v1)(4-(trifluorometta% ritlin-yl)metimiloate 0õ0 Nil [04221 1.,CMS (Method F, ES-APT): RT 2.85 min, m+H = 637.2; 1HNMR (400 MHz, CDC13): 6 8.87 (1H, d, J = 4.9 Hz), 8.14 (1H, br s), 7.72 (1H, dd, J = 4.9, 1.0 Hz), 7.46-7.41 (2H, in), 7.37-7.31 (2H, m), 7.29 (1H, s), 7.20-7.15 (2H, m), 6.52 (1H, d., J= 2.1 Hz), 5.50 (1H, dd, J
= 12.3, 2.1 Hz), 4.17 (1.H., d, J = 16.9 Hz), 3.88-3.83 (1H, m), 2.91 (1H, d, J = 16.9 Hz), 2.88-2.78 (2H, m), 2.6I-2.M (2H, m).
EX:Ample 11BR. (R)-(144-ehloronhenv1)-6-41-rttethy1-M-ovrazol-3-1)sulfonv1)-3,4a,5,6õ7,8-hexahvdro-11-1-pyrazolo13,4141 isoq tianolin-42-y11(4-(trifl uoromethybpv rid in-2-vijinethanonc o Q
N kin /
"-N
CI
[04231 . LCMS (Method F, ES-API): RI 2.60 min, m+H = 603.2; 1H NMR (400 MHz, CDC13): 6 8.88 (1H, d, J = 4.9 Hz), 8.14 (1H, br s), 7.68 (1H, dd, J = 4.9, 1.0 Hz), 7.47-7.41 (4H, m), 7.38 (1H, d, J = 2.3 Hz), 7.32 (1H, s), 6.56 (1H, d, j= 2.3 Hz), 6.55 (1H, d, J = 2.0 Hz), 5.55 (1H, dd, J = 12.5, 2.0 Hz), 4.23 (1H, d, J = 16.9 Hz), 3.96 (3H, s), 3.89-3.85 (1H, m), 2.95 (1H, d, J = 16.9 Hz), 2.94 (1H, d, J = 12.5 Hz), 2.89-2.80 (1H, m), 2.69-2.63 (1H, m), 2.51-2.47 (1H, m).
Example I IBS. (R).-(6-4111-pv razol-4-vDs I fonvI)-1-(4-11aorop e ny1)-4.4a,5.6.7,8-h ex a hvd ro-1 H-pyrazolo (3A-211sog inoli n-4a-%I)( py rid i n-2-v1)meth an one \v/
N
N, ,N
N N H
(,) [0424] LCMS (Method F, ES-API): RT 2.25 mm, m I-H = 505.0; I H NMR (400 MHz, CDC13): 8 11.12 (1H, br. S.), 8.65 (I H, ddd, J = 4.7, 1.6, 1.0 Hz), 8.36 (111, d, J = 0.6 Hi.), 7.88 -7.81 (21-1, m), 7.78 (1H, d, J = 0.6 Hz), 7.51 -7.39 (3H, in), 7.31 (IH, s), 7.20- 7.13(2H, m), 6.50 (1H, d, J = 2.0 Hz), 5.50 (1H, dd, J = 12.1, 2.0 Hz), 4.24 (iH, d, J =
17.0 Hz), 3.86 - 3.78 m), 2.91 (1H, d, J= 17.0 Hz), 2.86 - 2.74 (2H, m), 2.64- 2.45 (2H, m).
Example IIBT. (R)-(64(1-methy1-1 H-pyrazol-3-vDsultony1)-1-(4-(trifluorom et h vi)phenvi)-4,4a,5,6,7,8-hex ahvd ro- 1111-p vrazolo I 3,4:141isociainolin-4a-Y1)(Dvridin-2-y1)metha none Ciy.0 0 p rN-N
c\--) F3c [0425] LCMS (Method F, ES-API): RT 2.48 mm, m+H = 569.0; 1H NMR (400 MHz, CDC13): 8 8.67 (1H, ddd, J = 4.8, 1.8, 0.9 Hz), 7.89 (1H, dt, J = 7.9, 1.4 Hz), 7.83 (1H, td, J =
7.6, 1.8 Hz), 7.74 (2H, d, J = 8.4 Hz), 7.63 (2H, d, J = 8.4 Hz), 7.46 (1H, ddd, .1= 7.6, 4.8, 1.4 Hz), 7.38 (1H, d, J = 2.3 Hz), 7.37 (1H, s), 6.59 (1H, br. d, J = 2.3 Hz), 6.58 (1H, br. d, J = 2.3 Hz), 5.53 (1H, dd, J = 12.5, 2.0 Hz), 4.37(111, d, j= 17.1 Hz), 3.96 (311, s), 3.87 (1H, ddt, J =
8.5, 4.1,2.0 Hz), 2.98 - 2.80 (3H, m), 2.66(111, ddd, J = 12.6, 11.1, 3.5 Hz), 2.53 - 2.44 (1H, m).
Exanipk ii BU. (10-(643,4-difitiorophenvI)sulfonv1)-1-(4-fluorophen0-4,4a,5.6,7,8-hemihµ ro-111-inrazolo13A-21isog n-4a-8.1)( thiazid-4 ha none K\S 0 0 N
NI N *
%14 110426l LCMS (Method F, ES-API): RT 2.76 min, = 556.9; 1H NMR (400 MHz, CDC13): 6 8.87 (1H, d, J = 2.2 Hz), 8.24 (1H, d, J = 2.2 Hz), 7.56 - 7.46 (211, m), 7.46 - 7.39 (211, m), 7.29 -7.23 (211, m), 7.19 -7.12 (211, m), 6.52 (111, d, J = 2.1 Hz), 5.45 (114, dd, J =
12.4,2.1 Hz), 4.15 (1H, d, J= 17.0 Hz), 3.89 - 3.84 (111, m), 2.92 - 2.80 (2H, m), 2.73 (1H, d, J
= 12.5 Hz), 2.57 - 2.50 (2H, m).
Example I 1By. (R)-(64(1,2-dimethy1-1H-imidazol-4-v1)sulfonv1)-1-(4-fluoropheny1)-4,4a,5,6,7.8- hexahvdro-1H-pyrazolol3,4-g IISOQUinalin-4a-v1)(4-(triflu orom ethyl)pvtidin-2-ilmethanone NLf0 0 ,e N
NI I
104271 LCMS (Method F, ES-API): RT 2.28 mm, m+H = 601.1; 111NMR (400 MHz, CDC13): 6 8.87 (1H, d, J = 5.0 Hz), 8.15 -8.11 (111, m),7.70 - 7.65 (11I, m), 7.49- 7.40 (2171, m), 7.30(111, s), 7.21 - 7.14 (211, m), 6.51 (111, d, J = 2.1 Hz), 5.54 (1H, dd, J
= 12.6, 2.1 Hz), 4.23 (1H, d, J = 17.2 Hz), 3.83 (IH, ddt, J = 8.5, 4.0, 2.1 Hz), 3.58 (3H, s), 2.99 (1H, d, J = 12.6 Hz), 2.97 (1H, d, J = 17.2 Hi), 2.82 (1H, tdd, J = 14.8, 5.9,2.4 Hz), 2.70 -2.61 (1H, m), 2.47 - 2.43 (1H, m), 2.37 (3H, s).
Example 11 BW. (R)-(6-((l ,2-dimethiv1-111-im idazo1-5-v )s al fo tt,t, 1)- 1-(4-11 uorophett % 1)-4.4a.5,6.7,8 = hexahydro- I H-ps, razoloi 3,4=241isot) ui n431i11-4a-vil)(4-(tril1taoronaetin 13w riclin-2-S 1)methalloate g.;.O
1147--r"V's'N:
µN
[04281 LCMS (Method F, ES-API): RI 2.20 min, m+H = 601.0; 1H NMR (400 MHz, CDC13): 6 8.76 (1H, d, J = 5.0 Hz), 8.04 (1H, s), 7.72 - 7.65 (1H, m), 7.45 -7.41 (3H, m), 7.24 (1H, s), 7.22 - 7.13 (2H, m), 6.55 (1H, s), 5.60 (1H, dd, J = 12.9, 2.0 Hz), 4.08 (1H, d, J = 16.9 Hz), 4.01 -3.96 (1H, m), 3.40 (3H, s), 3.12 (1H, d, J = 13.0 Hz), 2.96 - 2.82 (3H, m), 2.69 - 2.59 (1H, m), 2.12 (3H, s).
Example 11BX. (R)-(144-fluorophenv1)-64(1-methy1-1H-imidazol-2-yl)sulfonyll-4,4a.,5.6,7.8-hexahvdro-1H-pvrazolo13,4-21isonuino1in-4a-v1)(4-(tril1uoromethyl)m ridin-2-v1)methanonc , N
Ni /N
41, [04291 LCMS (Method F, ES-API): RT 2.49 min, m+H = 587.0; 1H NMR (400 MHz, CDC13): 6 8.83 (1H, d, J = 5.0 Hz), 8.15 -8.13 (1H, m), 7.70 - 7.64 (1H, m), 7.51 -7.42 (2H, m), 7.3() (1H, s), 7.23 - 7.14 (2H, m), 7.00 (1H, d, J = 1.1 Hi), 6.90 (1H, d, J =
1.1 Hz), 6.57 (1H, d, = 2.1 Hz), 5.60 (1H, dd, J = 13.0, 2.1 Hz), 4.24 (1H, d, J= 17.0 Hz), 3.93 (1H, ddt, .1= 9.2,4.2, 2.1 Hz), 3.80 (3H, s), 3.57 (1H, d, J = 13.1 Hz), 3.28 -3.15 (1H, m), 3.01 (1H, d, J = 17.0 Hz), 2.87 (1H, dddd, .1= 15.1, 12.6, 6.1, 2.4 Hz), 2.58 -2.51 (1H, m).
Example 11BY. (R)-(64(1-eth11-1H-imidazol-4-yl)sulfony1)-1-(4-fluoronhem I .--1.-1a.5,6.7,8-hexalivdro-1H-Dvrazolo13.4-21isotiuinolin-4a-y1)(4-(trifinoromethvOpyridin-2-v1)methanone N.N
N/ I I ) --104301 LCMS (Method F, ES-API): RT 2.34 min, m+H = 601.1; 1H NMR (400 MHz, CDC13): 6 8.87 (1H, d, J = 4.9 Hz), 8.14 (1H, m), 7.67 (1H, dd, J= 4.9, 1.0 Hz), 7.49 (1H, d, J =
1.4 Hz), 7.47-7.42 (2H, m), 7.40 (1H, d, J = 1.4 Hz), 7.30(11, s), 7.20-7.14 (2H, m), 6.51 (11, d, J = 2.1 Hz), 5.58 (1H, dd,J = 12.4,2.1 Hz), 4.24 (1H. d, J = 16.9 Hz), 4.02 (2H, q, J = 7.4 Hz), 3.88-3.83 (1H, m), 3.03 (iH, d, J = 12.4 Hz). 2.96 (1H, d, J = 16.9 Hz), 2.87-2.78 (11-1, m.), 2.72-2.65 (1H, m.), 2.50-2.46 (1H, m), 1.49 (3H, 1, J = 7.4 Hz).
Example 11BZ. (R)-(64(1-ethv1-1H-pvrazol-4-yBsulfonv1)-144-fluorofihenv1)-4.4a,5,6,7,8-hexahvdro-lH-pyrazolot3.4-glisoauinan-4a-y1)(thiazol-4-v1)methanone S

N N
/ -Sr p [04311 LCMS (Method F, ES-API): RT 2.34 min, m+H = 539.0; 1H NMR (400 MHz, CDC13): 8 8.89 (1H, d, J = 2.2 Hz), 8.26 (1H, d, J = 2.2 Hz), 7.73 (1H, s), 7.67 (1H, d, J = 0.7 Hz), 7.48 - 7.39 (2H, m), 7.30 (1H, s), 7.21 -7.12 (2H, m), 6.52 (1H, d, J =
2.2 Hz), 5.42 (1H, dd, J = 12.1, 2.2 Hz), 4.25 -4.13 (3H, m), 3.80 (1H, ddt, J = 10.5, 6.4,2.0 Hz), 2.94- 2.81 (2H, m), 2.63 (1H, d, J = 12.1 Hz), 2.55 -2.38 (2H, m), 1.52 (3H, t, J = 7.3 Hz).
Example 11CA. (R)4144-11norophem I )-6-((1-propvi-I11-pyrazoi-4-vi)sollonv1)-4.4:45,6,718-hexahvdro-1H-pwrazolo13A-glisoquinolin-4a-v1)(pyridi n-2-v1)metbanone NS*
N, I I rp N
\--c) 104321 LCMS (Method 1,, ES-AP1): RT 2.36 mm, m+H = 547.2; 1H NMR (400 MHz, CDC13): ö 8.66 (1H, dq, J =4.8,0.8 Hz), 7.90 (1H, dt, J= 8.0, 1.2 Hz), 7.84 (1H, td, J = 7.6, 1.6 Hz), 7.68 (2H, dd, J = 14.0,0.8), 7.49-7.42 (3H, m), 7.30 (1H, s), 7.19-7.14 (2H, m), 6.49 (1H, d, J = 2.0 Hz), 5.46 (1H, dd, J = 12.0, 2.0 Hz), 4.32 (1H, d, J = 16.8 Hz), 4.07 (2H, t, J = 7.0 Hz), 3.79-3.75 (1H, m), 2.91 (1H, d, .1= 16.8 Hz), 2.88-2.80 (1H, m), 2.67 (1H, d, .1= 12.0 Hz), 2.50-2.39 (2H, m), 1.89 (2H, sex, J = 7.6 Hz), 0.91 (3H, t, J = 7.6 Hz).
Example 11CB. (R)-(144-11tiorophenv1)-64(1-(2-methoxyethyl)-1H-pyrazol-4-NBsulfony1)-4,4a,5,6,7.8-hevalivdro-1H-pyrazolo[3,4-idisoquinolia-4a-y1)(PYridin-2-0)methanone op _LN,N

104331 LCMS (Method F, ES-API): RI 2.19 min, m+H = 563.3; 1H NMR (400 MHz, CDC13): 8 8.67 (1H, d, J = 4.9, 1.7, 0.9 Hz), 7.92-7.89 (1H, m), 7.84 (1H, dt, J = 7.5, 1.7 Hz), 7.81 (1H, s), 7.66 (1H, d, J= 0.5 Hz), 7.49-7.42 (3H, m), 7.31 (1H, s).7.19-7.13 (2H, m), 6.49 (1H, d, J = 2.1 Hz), 5.46 (1H, dd, J = 12.1,2.1 Hz), 4.32 (1H, d, J = 16.9 Hz), 4.28 (2H, dd, J =
4.9 Hz), 3.79-3.75 (1H, m), 3.71 (2H, cid, J = 4.9 Hz), 3.32 (3H, s), 2.91 (1H, d, J = 16.9 Hz), 2.88-2.78 (1H, m), 2.66 (1H, d, J = 12.0 Hz), 2.51-2.39 (2H, m).
Example 11CC. (R)-(643,4-dichlorophenyl)stilfoliy1)-1-(4-fluoropheny1)-4,4a,5.6.7.8-hexahydro-114-pyrazo1o1i.4.:41isoqttinotin-4a-y1)(1-methv1- I I l-pvrazol-4-v11)methanone Ni000 CI
N/ I N
µN CI
104341 LCMS (Method F, ES-API): RT 2.52 mm, m+H = 586.1; 1H NMR (400 MHz, CDC13): ö 7.88 (1H, s), 7.87 (1H, d, J = 1.8 Hz), 7.84 (1H, d, J = 0.5 Hz), 7.63-7.58 (2H, m), 7.46-7.41 (2H, m), 7.35 (1H, s), 7.22-7.16(2H, m), 6.50 (1H, s), 4.55 (1H, dd, J = 11.4, 1.7 Hz), 3.89 (311, s), 3.89-3.82 (I m), 3.29 (111, d, J = 17.2 Hz), 2.76 (111, d, J = 17.2 Hz), 2.62-2.45 (311, m), 2.42-2.37 (1H, m).
Example 11CD. (R)-(144-fluorophenv1)-64(1-isopropy1-1H-pyraza1-4-vbsulfonv1)-4.4a.5.6.7.8-hexahvd ro-1H-pyrazolol isoqu noi-4a-v1)(ovridin-2-vbmetha none 1C)0 !I,0 N Ii I I N
104351 LCMS (Method F, ES-API): RI 2.41 min, m+H = 547.1; 1H NMR (400 MHz, CDC13): 8 8.67 (1H, ddd, J = 4.8, 1.8, 0.9 Hz), 7.90 (1H, ddd, 3 = 7.9, 1.3, 0.9 Hz), 7.84 (1H, td, I = 7.5, 1.8 Hz), 7.73 (1H, s), 7.66 (1H, d,J = 0.7 Hz), 7.52 -7.41 (3H, m), 7.30 (1H, s), 7.21 -7.12 (2H, m), 6.50 (1H, d, 1=2.1 Hz), 5.47 (1H, dd,1 =12.0, 2.1 Hz), 4.49 (1H, hept, J = 6.9 Hz), 4.32 (1H, d, J = 17.0 Hz), 3.80- 3.74(1H, m), 2.93 (1H, d, I = 17.0 Hz), 2.88 -2.79 (1H, m), 2.68 (111, d, J = 12.0 Hz), 2.58 - 2.39 (2H, in), 1.52 (6H, d, J = 6.9 Hz).
Examples 110E, 11CF and 11CG.

(R)-(1-(4-fluorophenyI)-6-((2-methy1-2H-1,2,3-triazol- 0 0 4-yl)sulfony1)-4,4a,5,6,7,8- N .
110E hexahydro- I H-N., I W
pyrazoio[3,4-disoquinol in- 'N
4a-y1)(4-(trifluoromethyppyridin-2- *
yl)methanone (R)-(1-(4-fluoropheny1)-6-((1-methy1-1H-1,2,3-triazol- I 0 0õ0 S-yl)sulfonyI)-4,4a,5,6,7,8-N
11CF hexahydro- I Fl- N"
pyrazolo[3,4-g]isoquinolin- .. 'N
4a-y1)(4-(trifluoromethyl)pyridin-2-yOrnethanone (R)-(1-(4-fluoropheny1)-6-0 0õ0 4-yl)sulfony1)-4,4a,5,6,7,8- I N
I iCG
hexahydro-1H¨ N /
ss,N
pyrazolo[3,4-g]isoquinolin- I sNi 4a-y1)(4-(trifluoromethyl)pyridin-2- j=
yl)methanone I F
104361 Prepared from Preparation 1 of Intermediate 89. LCMS (Method F, ES-API): RT 2.55 min, m-111 = 588.0; 1E1 NMR (400 MHz, CDC13): 5 8.89 (114, dt, J 5.0, 0.8 Hz), 8.15 - 8.13 (1H, m), 7.81 (111, s), 7.70(111, ddd, J = 5.1, 1.7, 0.8 Hz), 7.48 - 7.42 (2H, in), 7.30 (1H, s), 7.22 - 7.13 (211, m), 6.54 (1H, d, J = 2.2 Hz), 5.59 (III, dd, J = 12.7, 2.2 Hz), 4.25 (3H, s), 4.22 (1H, d, J = 17.0 Hz), 3.90 (IH, ddt, J = 10.6, 6.0, 2.0 Hz), 2.99 (1H, d, J = 12.7 Hz), 2.95 (1.H, d, J =
17.0 Hz), 2.84 (1H, tdd, J= 12.7, 5.9, 3.0 Hz), 2.74 - 2.67 (1H, m), 2.52 (1H, br. dt, J = 14.6, 2.7 Hz).
104371 Prepared from Preparation 2 of Intermediate 89. LCMS (Method F, ES-API): RT 2.50 min, m+H 588.2; III NMR. (400 MHz, CDC13): 6 8.80 (1H, d, J = 4.9 Hz), 8.11 (111, m), 7.91 (1H, s), 7.73-7.71 (IF!, m), 7.47-7.41 (211, m), 7.28 (1H, s), 7.21-7.16(2K, m), 6.56 (1E1, s), 5.51 (1H, dd, J = 12.7, 2.1 HZ), 4.13 (111, d, J = 16.9 Hz), 4.11 (3H, s), 4.01-3.93 (11-1, m), 3.09(111, d, J = 12.7 Hz), 2.92 (1H, d,J = 16.9 Hz), 2.87-2.81 (2H, m), 2.65-2.60 (1H, m).
104381 Prepared from Preparation 3 of Intermediate 89. LCMS (Method F, ES-API): RT 2.41 mm, m+H = 588.2; 1H NMR (400 MHz, CDC13): 6 8.87 (111, d, J = 4.9 Hz), 8.15 (1H, m), 7.89 (1H, s), 7.70-7.69(111, m), 7.48-7.43 (2H, m), 7.31 (1H, s), 7.21-7.15 (2H, m), 6.54(1H. s), 5.61 (1H, dd, J = 12.5, 2.0 Hz), 4.23 (1H, d, 3= 16.9 Hz), 4.15 (3H, s), 3.95-3.87 (1H, m), 3.14 (1H, d, J = 12.5 Hz), 2.96 (1H, d,J = 16.9 Hz), 2.88-2.78 (211, m), 2.57-2.48 (1H, m).
Examples 11CH, 11C1 and 11CJ.

(R)-(64(2-ethy1-2H-1,2,3- - N I r, 11.0 triazol-4-yl)sulfony1)-1-(4- N
fluoropheny1)-4,4a,5,6,7,8- NI I N , 11CH hexahydro-1H- '11 pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone (R)-(6-((1 -cthyl- 1 H- 1,2,3- õ
N" I
triazol-5-yl)sulfony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-11C1 hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-yl)methanone (R)-(6-((1-ethy1-111-1,2,3- _t L,.,.0 triazol-4-yl)sulfony1)-1-(4- N
fluoropheny1)-4,4a,5,6,7,8- NI N oN
I 1 C.,1 hexahydro-1H- µ11 pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-yl)methanone [04391 Prepared from Preparation 1 of Intermediate 90. ',CMS (Method F. ES-API): RT 2.44 min, m+H = 534.0; IH NMR (400 MHz, CDC13): 6 8.68 (1H, ddd, J = 4.8, 1.7, 0.9 Hz), 7.88 (1H, ddd, J = 7.9, 1.7, 0.9 Hz), 7.84 (1H, td, J = 7.4, 1.7 Hz), 7.80 (1H, s), 7.51 - 7.40 (3H, m), 7.31 (1H, s), 7.22 - 7.12 (2H. m), 6.51 (1H, d, J = 2.1 Hz), 5.61 (1H, dd, J.=
12.7,2.1 Hz), 4.51 (2H, q, J = 7.3 Hz), 4.32 (1H, d, J = 17.0 Hz), 3.90 (1H, ddt, J = 11.0,6.0, 2.0 Hz), 3.00- 2.90 (2H, m), 2.84(111, tdd, J = 12.7, 6.0,3.0 Hz), 2.70 (114, ddd, j:::: 12.7, 11.0,3.3 Hz), 2.50 (1 dt, .1= 14.3, 3.0 Hz), 1.59 (3H, t, J = 7.3 Hz).
[0440] Prepared from Preparation 2 of Intermediate 90. LCMS (Method F, ES-API): RT 2.42 min, = 534.1; 11E1 NMR (400 MHz, CDC13): 6 8.61 -8.55 (1H, m), 7.88 (1H, s), 7.86 - 7.79 (2H, m), 7.52 - 7.40 (31-I, m), 7.27 (1H, br. s), 7.22- 7.13 (211, in), 6.54 (1H, br. s), 5.62 (111, dd, = 12.6, 2.0 Hz), 4.50- 4.36 (211, m), 4.21 (1H, d, j = 16.9 Hz), 3.98 - 3.89 (1H, m), 3.13 (1H, d, J = 12.7 Hz), 2.96 -2.76 (3H, m), 2.64 -2.56 (1H, m), 1.51 (3H, t, J = 7.3 Hz).
[0441] Prepared from Preparation 3 of intermediate 90. LCMS (Method F, ES-API): RT 2.32 min, m-FH = 534.1; 1H NMR (400 MHz, CDC13): 8 8.66 (1H, ddd, .11= 4.8, 1.8, 0.9 Hz), 7.92 -7.87 (2H, m), 7.83 (1H, td, J = 7.7, 1.8 Hz), 7.49 - 7.40 (3H, m), 7.30 (1H, s), 7.21 -7.12 (2H, m), 6.51 (1H, br. s), 5.59 (1H, dd, .1= 12.6, 2.1 Hz), 4.45 (2H, q, J= 7.4 Hz), 4.31 OH, d, .1=
16.9 Hz), 3.98 3.87 (1H, m), 3.14 (1H, d, J = 12.6 Hz), 2.94(1H. d, J = 16.9 Hz), 2.87 2.78 (21, m), 2.56 - 2.44 (1H, m), 1.59 (31, t, J = 7.4 Hz).
Examples lICK, I 1CL and 11CM.

(R)-(6-((2-ethy1-2H-1,2,3-triazol-4-yl)sulfony1)-1-(4- I 0 r fluoropheny1)-4,4a,5,6,7,8-hexahydro-1H-IICK N I
pyrazolo [3,4-g] isoqu inolin- 'N
4a-y1)(4-(trifluoromethyppyridin-2- y yl)methanone (R)-(64(1-ethy1-1H-1,2,3-triazol-5-yl)sulfony1)-1-(4- ==== 0 0, \) fluoropheny1)-4,4a,5,6,7,8- N\g/ N

licxa hydro- 1H- Nl .."-C =
I ,N
pyrazolo[3,4-disoquinolin-4a-yI)(4-(trifluoromethyl)pyridin-2- *
yl)methanone ...... F

(R)-(6-((1-ethy1-1H-1,2,3-triazol-4-yl)sulfony1)-1-(4- 0 fluoropheny1)-4,4a,5,6,7,8- N N
hexahydro-1H-s' pyrazolo[3,4-g]isoquinolin .. I I-4a-y1)(4-(trifluoromethyppyridin-2-yl)methanone 104421 Prepared from Preparation I of Intermediate 90. LCMS (Method F, ES-API): RT 2.67 min, m+II = 602.0; LHNMR (400 MHz, CDC13): 6 8.89(111, d, J = 5.1 Hz), 8.16-8.12 (111, in), 7.81 (114, s), 7.71 (1 ddd, J = 5.0, 1.8, 0.7 Hz), 7.49 - 7.40 (2H, m), 7.30(111, g), 7.23 -7.15 (211, ro.), 6.54 (1H, d, J = 2.1 Hz), 5.59(111, dd, j =12.7, 2.1 Hz), 4.51 (211, q, J = 7.3 Hz), 4.22 (11.1, d, J = 17.0 Hz), 3.95 - 3.84 (111, rn.), 2.97 (1H, d, J = 12.7 Hz), 2.95 (111, d, J = 17.0 Hz), 2.89- 2.78 (111, rn), 2.73 - 2.66 (1H, m), 2.58 - 2.47 (111, m), 1.59 (3I1, t, J = 7.3 Hz).
[04431 Prepared from Preparation 2 of Intermediate 90. LCMS (Method F, ES-API): RT 2.62 min, m-FIT = 602.1; lB NMR. (400 MHz, CDC13): 6 8.81 (11i, d, J = 5.1 Hz), 8.12 -8.11 (111, in), 7.89(111, s), 7.72 (III, ddd, J = 5.1, 1.8, 0.7 Hz), 7.48 - 7.39 (211, in), 7.28 (1171, s), 7.24 -7.13 (211, ro.), 6.57(111, br. s), 5.54 (1H, dd, J = 12.8, 2.1 Hz), 4.53 -4.40 (211, m), 4.14(111, d, J
=16.9 Hz), 4.01 3.90 (1H, m), 3.11 (1.H, d, J = 12.8 Hz), 2.92 (1H, d, J =
16.9 Hz), 2.86 - 2.79 (211, m), 2.68 - 2.55 (1H, in), 1.52 (3H, t, J = 7.2 Hz).
[0444j Prepared from Preparation 3 of Intermediate 90. LCMS (Method F, ES-API): RT 2.53 min, m+11= 602.1; IH NMR. (400 MHz, CDC13): 6 8.88 (1H, br. d, J 5.1 Hz), 8.15 - 8.14 (1H, in), 7.91 (I H, s), 7.69 (111, ddd, J = 5.1, 1.8, 0.8 HZ), 7.49 - 7.41 (21-1, m), 7.31 (1H, s), 7.23 -7.13 (21-1, m),6.54 (1H, br. s), 5.62(111, dd, J = 12.8, 2.1 H.z), 4.46 (2H, q, J = 7.4 Hz), 4.23(111, d, J=' 17.0 Hz), 3.94 - 3.88 (1H, m), 3.17 (IH, d, J= 12.8 Hz), 2.97 (1H, d, J
= 17.0 Hz), 2.89 -2.80 (2H, m), 2.57 2.46 (111, m), 1.60 (311, t, J = 7.4 Hz).
Examples 11CN, 11C0 and 11CP.

(R)-(1-(4-fluoropheny1)-6-, ((2-propy1-2H-1,2,3-0 9, 0 triazol-4-Asulfonyl.)-11CN 4,46,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a- *
yl)(pyridin-2-yl)methanone (R)-(1-(4-fluoropheny1)-6- 1 R
01-propy1-1H-1,2,3-P
triazD1-5-yl)sulfony1)-N t\
4,4a,5,6,7,8-hexahydro- N
11C0 = L., hi' 1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-Amethanone (R)-(1-(4-fluoropheny1)-6-((1-propy1-1H-1,2,3- µNr_y!
triazol-4-yOsulfony1)- N
11C 4,4a,5,6,7,8-hexahydro- 11 I µ21µ1 P 'NJ
1H-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-yl)methanone [04451 Prepared from Preparation 1 of Intermediate 91. LCMS (Method F. ES-API): RT 2.54 min, m+H = 548.2; 1.H NMR. (400 MHz, CDC13): 6 8.68 (1H, ddd, J = 4.9, 1.6,0.9 Hz), 7.88 (1H, ddd, J = 7.9, 1.4, 0.9 HZ), 7.83 (1H, dt, J = 7.4, 1.6 Hz), 7.80 (1 n, s), 7.49-7.42 (3H, m), 7.30 (11-I, s), 7.20-7.14 (2H, m), 6.51 (111, d, J: 2.1 Hz), 5.60 (11-1, dd, J
= 12.5, 2.0 Hz), 4.42 (2H, t, I = 7.1 Hz), 4.32 (1.F!, d, J = 16.9 Hz), 3.92-3.87 (1H, m), 2.95 (1F.1, d, J = 12.5 Hz), 2.92 d, J = 16.9 Hz), 2.89-2.80 (1H, m), 2.71-2.64 (1H, m), 2.52-2.47 (1H, m), 2.00 (21-1, sext, J
= 7.1 Hz), 0.93 (311, t, J = 7.1 Hz).
104461 Prepared from Preparation 2 of Intermediate 91. LCMS (Method F, ES-API): RT 2.47 min, = 548.2; 1F.1 NMR (400 MHz, CDC13): 6 8.59 (1H, ddd, J 4.9, 1.6, 0.9 Hz), 7.88 s), 7.87-7.81 (2H, m), 7.48 (11-1, ddd, I = 6.8, 4.9, 2.1 Hz), 7.46-7.41 (2H, m), 7.27 (1H, s), 7.20-7.14 (2H, m), 6.54 (1H, br s), 5.61 (11I, dd, J = 12.7, 2.0 Hz), 4.40-4.29 (2H, m), 4.22 (1H, d, J = 16.9 Hz), 3.97-3.89 (1H, m), 3.12 (1H, d, J = 12.7 Hz), 2.91-2.81 (3H, m), 2.64-2.56 (1H, m), 1.92 (2H, dsext, J = 7.1, 0.7 Hz), 0.93 (3H, t, J = 7.1 Hi).
[9447] Prepared from Preparation 3 of intermediate 91. LCMS (Method F, ES-API): RT 2.37 min, m-FH = 548.2; 1H NMR (400 MHz, CDC13): 8 8.66 (1H, ddd, J = 4.7, 1.6, 0.9 Hz), 7.91-7.88 (2H, m), 7.83 (1H, dt, J= 7.5, 1.6 Hz), 7.48-7.42 (3H, m), 7.30 (1H, s), 7.19-7.14 (2H, m), 6.51 (111, s), 5.60 (1H, dd., J= 12.5, 2.0 Hz), 4.35 (2H, t, J = 7.1 Hz), 4.32 (1H, d, J= 16.9 Hz), 3.97-3.88 (1H, m), 3.12 (1H, d, J = 12.5 Hz), 2.94 (1H, d, J = 16.9 Hz), 2.88-2.79 (2H, m), 2.55-2.46 (1H, m), 1.96 (2H, sext, J = 7.1 Hz), 0.97 (3H, t, J = 7.1 Hi).
Examples 11C0.11CR and 11CS.
s-1.1 (R)-(1-(4-fluoropheny1)-6- -.11y0 ((2-propy1-2H-1,2,3- N
N
triazol-4-yl)sulfony1)-11CQ 4,4a,5,6,7,8-hexahydro-114-pyrazo 1.o[ 3 ,4-g] isoquinoli n -4a-yl)(thiazol-4-y1)methanone (R)-(1-(4-fluoropheny1)-6- 0 Rp ((1-propy1-1H-1,2,3-N ;SI NI
triazol-5-yl)sulfony1)- N/ I 21s1 11CR 4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-yl)(thiazol-4-yOmethanone (R)-(1-(4-fluoropheny1)-6-N o p ((1-propy1-1H-1,2,3-triazol-4-yl)sulfony1)- N I

i CS 4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-glisoquinolin-4a-y1)(thiazol-4-yOmethanone '97 1.04481 Prepared from Preparation 1 of intermediate 91. LCMS (Method F, ES-API): RT 2.45 min, m+H = 554.2; 1H NMR (400 MHz, CDC13): 8 8.90 (1H, d, .11= 2.1 Hz), 8.25(111, d, S = 2.1 Hz), 7.82 (1H, s), 7.47-7.42 (2H, m), 7.30 (1H, s), 7.20-7.14 (2H, m), 6.54 (1H, d, J = 2.1 Hz), 5.55 (1H, dd, .1= 12.7, 2.0 Hz), 4.43 (2H, t, J = 7.1 Hz), 4.21 (1H, d, J=
16.9 Hz), 3.95-3.90 (1H, m), 2.93-2.85 (3H, m), 2.69-2.63 (1H, m), 2.53-2.49 (1H, m), 2.01 (2H, sext, J
= 7.1 Hz), 0.94 (3H, t, S = 7.1 Hz).
[04491 Prepared from Preparation 2 of Intermediate 91. LCMS (Method F, ES-API): RT 2.38 mm. m+H = 554.2; 1H NMR (400 MHz, CDC13): 6 8.81 (111, d, J = 2.2 Hz), 8.22 (11, d, J = 2.2 Hz), 7.89 (1H, s), 7.47-7.42(211, m), 7.28 (1H, s), 7.21-7.15 (211, m), 6.57 (111, br s), 5.48 (1H, dd, S = 12.8, 2.0 Hz), 4.39-4.28 (2H, m), 4.12 (1H, d, J = 16.9 Hz), 4.01-3.93 (111, m), 3.06 (111, d, J = 12.8 Hz), 2.92-2.83 (3H, m), 2.66-2.57 (1H, m), 1.93 (2H, dsext, J =
7.1, 0.6 Hz), 0.94 (3H, t, J = 7.1 Hz).
[04501 Prepared from Preparation 3 of Intermediate 91. LCMS (Method F, ES-API): RT 2.29 min, m+H. = 354.2; 1H NMR (400 MHz, CDC13): : 8.88 (1H, d, J = 2.1 Hz), 8.26 (1H, d, J =
2.1 Hz), 7.90 (1 s), 7.48-7.42 (2H, m), 7.30 (1H, s), 7.20-7.14(211, in), 6.54 (1H, d, J = 1.4 Hz), 5.55 (1H, dd, J = 12.7,2.0 Iiz), 4.37(211, t, J = 7.1 Hz), 4.21 (Iii, d, J = 16.9 Hz), 3.96-3.91 (1H, m), 3.06(111, d, I = 1.7 Hz), 7.94-7.80 (311, m), 7 57-7.48 (11-T, m), 1 .97 (p, sex!, I = 7.1 Hz), 0.98 (3H. t, 5= 7.1 Hz).
Examples 11C1, ii ('I and 11CV.
(R)-(1-(4-fluoropheny1)-6-o 0 ((2-isopropyl-2H-I,2,3- N /
triazol-4-yl)sulfony1)-, sy=
11CT 4,4a,5,6,7,8-hexahydro-1H- N
pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-yl)methanone (R)-(1-(4-fluoropheny1)-6-((l-isopropy1-1H-1,2,3- a Ow0 triazol-5-yl)sulfony1)- N I 11, 11CU 4,4a,5,6,7,8-hexahydro-1 pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone (R)-(1-(4-fluorophcny1)-6-o 00) triazol-4-yl)sulfony1)-N
11C V 4,4a,5,6,7.8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-yl)methanone F
104511 Prcparcd from Prcparation 1 of Intcrmcdiatc 92. LCMS (Mcthod F, ES-API): RT 2.56 min, m+H = 548; 1H NMR (400 MHz, CDC13): ö 8.68 (ddd, J = 4.7, 1.8, 1.0 Hz, 1H), 7.92 -7.81 (m, 2H), 7.79 (s, 1H), 7.52 - 7.39 (m, 3H), 7.30 (d, J = 0.8 Hz, 1H), 7.22 - 7.11 (m, 2H), 6.52 (d, J = 2.2 Hz, 1H), 5.61 (dd, J = 12.7, 2.0 Hz, 1H), 4.86 (hept, J= 6.7 Hz, 1H), 4.33 (d, J =
17.0 Hz, 1H), 3.91 (ddt, J = 10.8, 6.1,2.1 Hz, 1H), 3.00 - 2.78 (m, 3H), 2.69 (ddd, J = 12.6, 11.0, 3.3 Hz, 1H), 2.50 (dt, J = 14.8, 2.7 Hz, 1H), 1.6 (d, J = 6.6 Hz, 6H).
[04521 Prepared from Preparation 2 of Intermediate 92. LCMS (Method F, ES-API): RT 2.49 min, m+H = 548; 1H NMR (400 MHz, CDC13): 8 8.64 - 8.59 (in, 1H), 7.86 (s, 1H), 7.85 - 7.82 (m, 2H), 7.54 - 7.47 (m, 1H), 7.46 - 7.41 (in, 2H), 7.29 -7.27 (m, 1H), 7.21 -7.13 (m, 2H), 6.55 (d, j = 1.5 Hz, 1H), 5.67 (dd, J = 12.7,2.1 Hz, 1H), 4.95 (hept, .1 = 6.7 Hz, 1H), 4.21 (d, J = 16.8 Hz, 1H), 3.96- 3.84 (m, 1H), 3.14 (d, J = 12.7 Hz, 1H), 2.95 - 2.84 (m, 3H), 2.61 (m, 1H), 1.56 (d, J = 6.7 Hz, 3H), 1.53 (d, J = 6.7 Hz, 3H).
[04531 Prepared from Preparation 3 of Intermediate 92. LCMS (Method F, ES-API): RT 2.43 .. min, m+H = 548.1; 1H NMR (400 MHz, CDC13): 8 8.67 (1H, ddd, J = 4.8, 1.8, 0.9 Hz), 7.91 -7.86 (2H, m), 7.83 (1H, td, J= 7.7, 1.8 Hz), 7.50 - 7.41 (3H, m), 7.31 (1H, s), 7.21 -7.13 (2H, m), 6.52 (1H, br. s), 5.61 (1H, dd, J = 12.6, 2.1 Hz), 4.86 (1H, hept, J = 6.7 Hz), 4.32 (1H, d, J =

16.9 Hz), 3.97- 3.89 (11-I, m), 3.15 (1H, d, J = 12.6 Hz), 2.94 (1H, d, J =
16.9 Hz), 2.91 -2.78 (2H, m), 2.58 - 2.44 (1H, m), 1.61 (3H, d, j = 6.7 Hz), 1.60 (3H, d, I = 6.7 Hz).
Example 11CW. (R)-(64(1-ethv1-1H-weraiol-5-0)sulfoloa)-1-(4-fluorophenv1)-4,4a,5,6,7,8-hemtliµ ro- I 11-pyrazolol3.4-21isoq i nolia-4a-8.1)(tlaiazol-4-v1)methanone fl N
=
I0454] LCMS (Method F, ES-API): RT 2.32 min, mill = 539.2; 1H NMR (400 MHz, CDC13): 6 8.81 (1H, d, J = 2.1 Hz), 8.22 (1H, d, J = 2.2 Hz), 7.47-7.42 (2H, m), 7.39 (1H, d, J =
2.0 Hz), 7.28 (1H, s), 7.20-7.14 (21, m), 6.63 (1H, d, J = 2.0 Hz), 6.55 (1H, d, J = 2.1 Hz), 5.46 (111, dd. J = 12.7, 2.0 H4 4.34-4.17 (2H, m), 4.16 (1H, d, J = 16.9 H4 3.94-3.89 (1H, m), 2.98 (1H, d, J = 12.9 Hz), 2.92-2.75 (3H, m), 2.60-2.56 (1H, m), 1.41 (3H, t, 3 =
7.2 Hz).
Example IICX. (R)-(144-fluorophenvb-6-((1-Dropv1-111-Dvrazol-4-vOsuifonv1)-4Aa,5,6,7,8-hexahydro-111-pyrazolo[3.4-elisoquinoin-4a-v1)(4-(trifluoromethvOpyridin-2-0)methanone N 11.0 S' Ni I N rts4 104551 LCMS (Method F, ES-API): RT 2.58 min, m+H = 615.2; In NMR (400 MHz, CDCI3): 6 8.88 (1H, d, J = 5.0 Hz), 8.17 - 8.13 (1H, m),7.73 - 7.66(311, m), 7.47- 7.40 (2H, m), 7.30 (1H, 0, 7.22 - 7.12 (2H, m), 6.51 (1H, d, J = 2.1 Hz), 5.45 (1H, dd, J =
12.1, 2.1 Hz), 4.21 (1H, d, J = 17.0 Hz), 4.09 (2H, t, J = 11.3 Hz), 3.78 (1H, ddd, J = 10.6, 5.3, 3.1 Hz), 2.93 (1H, d, J = 17.0 Hz), 2.83 (1H, dddd, J = 14.9, 12.5, 6.0, 2.4 Hz), 2.65 (1H, d, J =
12.1 HZ), 2.50 (111, br.
d, J = 15.6 Hz), 2.41 (1H, ddd, J = 12.8, 10.8, 3.5 Hz), 1.90 (2H, sextet, J =
7.4 Hz), 0.91 (3H, t, J = 7.4 Hz).
Example !WY. (R)-(144-fluorophenv1)-64(1-ineth v1-1H-ns razol-4-sl)sulfonvfl-4,4a,5,6,7,8-hexahvdro-1H-pyrazolo13,4-0isooni ElO1in-4a-v1gthiazo1-4-v1)methanone µ.N 0 0 N rNN I
%N
[04561 LCMS (Method F, ES-API): RT 2.02 min, m-I.H = 525.2; 1H NMR (400 MHz, CDC13): & 8.88 (111, d, J = 2.2 Hz), 8.26 (1H, d, J = 2.2 Hz), 7.69 (1H, 0, 7.66 (1H, d, J = 0.6 Hz), 7.47 - 7.40 (2H, m), 7.30 (1H, s), 7.21 - 7.12 (2H, m), 6.52 (1H, d, J =
2.2 Hz), 5.41 (1H, dd, J= 12.2, 2.2 Hz), 4.18 (1H, d, .1= 16.9 Hz), 3.93 (s, 3H), 3.80 (1H, ddt, J= 8.5, 4.4, 1.9 Hz), 2.94 - 2.80 (211, m), 2.63 (1H, d, J = 12.2 Hz), 2.56 - 2.38 (2H, m).
Example 11(2. (R)-(144-fluoropheav1)-641-propv1-1H-pyrazol-4-yl)sulfonv1)-4,4a,5,6.7,8-hexahvdro-111-pyrazolo13.4-g1isoquinoli n-4a-v1)(thiazo1-4-thinetha none Ks -11 \N 00 N
N I I N
[04571 LCMS (Method F, ES-API): RT 2.31 min, m+H = 553.2; 1H NMR (400 MHz, CDC13): 8 8.90 (1H, d, J = 1.6 Hz), 8.27 OH, d, J = 2.0 Hz), 7.72 (1H, s), 7.68 (1H, d, J = 0.5 Hz), 7.46-7.42 (2H, m), 7.30 (1H, s), 7.20-7.15 (211, m), 6.52 (1H, d, J = 2.0 Hz), 5.43 (1H, dd, J
= 12.4, 2.0 Hz), 4.19 (1H, d, J = 16.8 Hz), 4.09 (2H, t, J= 7.1 Hz), 3.82-3.78 (1H, m), 2.94-2.81 (2H, m), 2.61 (1H, d, J = 12.4 Hz), 2.53-2.48 (1H, m), 2.44-2.37 (1H, m), 1.91 (2H, sext., .1= 7.2 Hz), 0.92 (3H, t, J = 7.2 Hz).
Example 11DA.
s¨

(R)-(1-(4-fluoropheny1)- 0 0 6-((2-methy1-2H-1,2,3-triazol-4-yl)sulfony1)-Isomer A m-S N
4,4a,5,6,7,8-hexahydro-1F1-pyrazolo[3,4-disoquinolin-4a- --y1)(thiazol-4-yl)methanone (R)-(1-(4-fluoropheny1)-641-methy1-1H-1,2,3- N 0 Rwp triazol-5-yl)sulfony1)-4,4a,5,6,7,8-hexahydro- N I
Isomer B N
1H-pyrazolo[3,4-g]isoquinolin-4a-y1)(thiazol-4-Amethanone (R)-(1 -(4-fluoropheny1)-641-methyl-1H-1,2,3- N 0 0,,0 triazol-4-yl)sulfony1)- R
Isomer C
4,4a,5,6,7,8-hexahvdro- N, I j *NE µ,N
N
1H-pyrazolo[3,4-gli soquinol in-4o-yl)(thiazo1-4-yl)methanone 104581 Prepared from Preparation 1 of Intermediate 89. LCMS (Method F, ES-API): RT 2.16 min, m-I-1-1 = 526.2; 111 NMR (400 Milz, CDC13): 8.90 (1 171, d, J = 2.2 Hz), 8.25(111, d, .1= 2.2 Hz), 7.82 (111, s), 7.47-7.42(211, m), 7.30 (1H, s), 7.20-7.14(211, m), 6.54 (111, d, J = 2.1 Hz), 5.55 (111, dd, 1 = 12.7, 2.1 Hz), 4.25 (31-1, s), 4.20(111, d, J = 16.9 Hz), 3.96-3.90(111, m), 2.93-2.85 (311, m), 2.73-2.66 (111, m), 2.54-2.49 (1 rn).
Example 11DB.

=-=:7\
(R)-(1.-(4-fluorophenyI)-6-= , o 0 ((2-methy1-2H-1,2,3-triazol-IN
Isomer 4-ypsulfony1)-4,4a,5,6,7,8- N
A hexahydro-111-pyrazolo[3,4-g]isoquinolin-4a-y1)(pyridin-2-yl)methanone IF
(R)-(1-(4-fluoropheny1)-6-0 , (( 1 -methy1-1H-1,2,3-triazol- N
Isomer 5-ypsulfony1)-4,4a,5,6,7,8- N I y :N
hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-yI)(pyridin-2-yl)metharion.e (R)-(1-(4-fluoropheny1)-6-(0-methy1-1H-1,2,3-triazo1-1 Isomer 4-ypsulfony1)-4,4a,5,6,7,8- I N' I N'SYN

hexahydro-1H- 11 pyrazolo[3,4-disoquinolin-42-y1)(pyridin-2- I *
yl)methanone F
[04591 Prepared from Preparation 1 of Intermediate 89. LCMS (Method F. ES-API): R.T 2.26 min, m+H = 520.0; 1.H NMR. (400 MHz, CDCI3): 6 8.67 (1H, ddd, J = 4.9, 1.6, 1.0 Hz), 7.88 (1H, ddd, J = 8.0, 1.6, 1.0 HZ), 7.83 (1H, dt, J = 7.4, 1.6 Hz), 7.80 (1 n, s), 7.49-7.42 (3H, m), 7.30 (11-I, s), 7.20-7.14 (2H, m), 6.51 (111, J= 2.1 Hz), 5.60 (11-1, dd, J =
12.4, 2.01-1z), 4.31 (1H, d, J = 16.9 Hz), 4.24 (3H, s), 3.92-3.87 (1H, m), 2.98 (1H, d, J = 12.6 Hz), 2.93 (1H, d, 16.9 Hz), 2.89-2.80 (1H, m), 2.74-2.68 (III, m), 2.53-2.48 (IH, m).
Example IIDC.

(R)-(1-(4-fluoropheny1)-6- , ((2-propy1-2H-1,2,3-triazol-4-yl)sulfony1)-4,4a,5,6,7,8- ====N 0 0 0 N
Isomer hexahydro-1H- N =
NI I 1_ pm A pyrazolo[3,4-g]isoquinolin- .. 'N
4a-y1)(4-(trifluoromethyppyridin-2- \
yl)methanone (R)-(1-(4-fluoropheny1)-6-((1-propy1-1H-1,2,3-triazol-5-yl)sulfonyl.)-4,4a,5,6,7,8-0 0õ0 hexahydro-1H- N N
Isomer pyrazolo[3,4-g]isoquinolin- N I2,1 4a-y1)(4-(trifluoromethyl)pyridin-2- *
yl)methanone (R)-(1-(4-fluoropheny1)-6--propy1-111-1,2,3-triazol-4-yl)sulfony1)-4,4a,5,6,7,8- 0 0õ0 hexahydro-1H- -V N
Isomer N
pyrazolo[3,4-g]isoquinolin- N/ I `:1\1 =-".
4a-y1)(4-(trifluoromethyl)pyridin-2-yOmethanone [04601 Prepared from Preparation 1 of Intermediate 91. LCMS (Method F, ES-API): RT 2.75 min, m+H = 616.2; 1H NMR (400 MHz, CDC13): 6 8.89 (1H, d, .1= 4.9 Hz), 8.14 (1H, m), 7.82 (1H, s), 7.71-7.70 (1H, m), 7.47-7.42 (2H, m), 7.30 (1H, s), 7.21-7.15 (2H, m), 6.53 (IH, d, J =
2.1 Hz), 5.58 (1H, dd, J = 12.5, 2.0 Hz), 4.42 (2H, t, J = 7.1 Hz), 4.22 (1H, d, J = 16.9 Hz), 3.92-3.87 (111, in), 2.96 (111, br s), 2.93-2.92 (III, m), 2.88-2.79 OIL m), 2.70-2.64 (111, m), 2.54-2.50 (1H, m), 2.01 (2H, sext, J = 7.1 Hz), 0.93 (3H, t, J = 7.1 Hz).
Example 12. (RHI-(4-fluoraohenv1):6-0-(trifluoromethyl)ohenvi)sulfony1)-4,4a.,5,617.8-hexahvdro-1H-pvrazolot3.4-glisoquinolin-4a-vp(thiazo/-2-viimethanone p 0 N -\\S CF3 NI I
Sji [04611 2-Bromothiazo1e (187 mg, 1.139 mmol) in dry ether (2 mI,) was added to butyllithium(1.6M in hexanes) (729 ti, 1.167 mrnol) in dry ether (4 mL) at -78 C. The reaction mixture was stiffed at -78 C for 45 minutes. A solution of (R)-methyl 1-(4-fluorophenyl)-6-03-(trifluoromethyl)phenyl)sulfony1)-4,4a,5,6,7,8-hexahydro-1H-pyrazol o[3,4-g]
isoqu inoli ne-4a-carboxylate (200 mg, 0.373 mmol) in dry ether (4 mlõ) was added dropwise and the reaction mixture was stirred for 30 minutes at -78 'C. Water (20 mL) was added and the reaction mixture was stirred at room temperature for 10 minutes. The aqueous layer was extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with brine (30 mL), dried (magnesium sulfate), and solvent removed to give a yellow oil. The crude product was purified first by chromatography on silica gel (gradient: 0 to 40% isohexane in ethyl acetate) followed by preparative H.PLC (Waters, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 um, 19x50 mm column, 40-65% acetonitrile in water) to afford (R)-(1-(4-fluoropheny1)-6-(trifluoromethyl)phenyl)sulfony1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-g]isoquinolin-4a-.. y1)(thiazol-2-yOmethanone (127 mg) as a pale yellow solid. LCMS (Method F, ES-API): RT
2.73 min, m+H = 589.0; 1H NMR (400 MHz, CDC13); 8 8.04 (1H, d, I = 3.1 Hz), 7.97 (1H, s), 7.90 (1H, d, .1= 7.9 Hz), 7.81 (1H, d, .1= 7.9 Hz), 7.70 -7.59 (2H, m), 7.46 -7.39 (2H, m), 7.30 (1H, s), 7.13 -7.19 (2H, m), 6.53 (1H, d, 1= 2.2 Hz), 5.54 (1H, dd, J = 12.4, 2.0 Hi.), 4.21 (1H, d, J = 16.8 Hz), 3.93 -3.89 (1H, m), 2.95 -2.84 (2H, m), 2.80 (1H, d, .1= 12.5 Hz), 2.61 -2.52 (2H, m).
[04621 The following examples were similarly prepared from the appropriate intermediates:
Example 12A. (10-(144-fluoroohenv1)-6-(m-tolvlsullonv1)-4.4a,5.6.7,8-hexahvdro-pyrazolol34-21isoquinolin-4a-y1)(thiazo1-2-v1methanone N"Si iot Ns [04631 I.,CMS (Method F, ES-API): RT 2.65 min, m+H = 535.0; 1H NMR (400 MHz, CDC13): 8 8.05 (111, d, J = 3.1 Hz), 7.66(111, d, J = 3.1 Hz), 7.54- 7.47 (21I, m), 7.44- 7.40 (211, m), 7.36 - 7.34 (211, in), 7.29 (111, s), 7.19 - 7.13 (211, m), 6.51 (iH, d, J = 2.3 Hz), 5.52 (1H, dd, J = 12.3, 2.1 Hz), 4.22 (1H, d, J = 16.8 Hz), 3.89 - 3.84 (1H, rn), 2.93- 2.84(2H, m), 2.71 (1H, d, J = 12.3 Hz), 2.56 - 2.43 (211, m), 2.41 (311, s).
Example 12B. (R)-(1-(4-11aorophetiv1)-643-tnethoxvphenvOsulfoitel)-4,4a,5,6,7,8-hexahvdro-1 11-1}µ, razolo[3.4-ttlisoquivonlin-4a-yll(thiatol-2-0)methanone çiç0 0õ0 \s/ ome [0464] LCMS (Method F, ES-API): RT 2.57 min, m+H = 551.0; 111NMR (400 MHz, CDC13): 68.04 (1H, d, J = 3.1 Hz,), 7.66(111, d, J = 3.1 Hz), 7.44 - 7.35 (314, m), 7.31 -7.27 (2H, m), 7.21 - 7.14 (3H, m), 7.07 (1H, ddd, J = 8.2, 2.6, 1.0 Hz), 6.52 (1H, d, J = 2.1 Hz), 5.50 (1H, dd, J = 12.4, 2.1 Hz), 4.22 (1H, d, J = 16.8 Hz), 3.89- 3.83 (4H, m), 2.93 -2.82 (2H, m), 2.74(1 H, d, J= 12.4 Hz), 2.53 -2.47 (2H, m).
I S Example 12C. (R)-(6((3-fitioro-4-metht Iphenvi)stalfon% 11)-1-(4-fluoroplitnvl)-4,4a,5,6.7.8-hek a Ã3 ilro-111-ovrazolloI3.4-tdisotao411-thithint4l-2-0)metim none 2 (I o (-14 0 0, 0 , F
N

µ14 [04651 I,CMS (Method F, ES-API): RT 2.70 min, m+H = 552.9; 1H NMR (400 MHz, CDC13): 8 8.04(111, d, J = 3.1 Hz), 7.67(111, d, J = 3.1 Hz), 7.43 - 7.38 (311, m), 7.34- 7.26 (3H, m), 7.19 - 7.13 (2H, m), 6.52 (111, d, J = 2.2 Hz), 5.50 (1H, dd, J =
12.4, 2.2 Hz), 4.21 (1H, d, J = 16.8 Hz), 3.87 (1H, ddt, J = 8.5, 4.3, 1.9 HZ), 2.93- 2.83 (2H, m), 2.74 (1H, d, J = 12.4 Hz), 2.54 - 2.48 (2H, m), 2.32 (3H, d, J ¨ 1.8 Hz).
Example 12D. (R)-(1-(41-fluoronhenv1)-6-(pheavlsulfonv1)-4.4a,546,7,8-hexalivdro-1H-nvrazolo13,4-illisonoinolin-42-v1)(thiazo1-2-v1)methanone (to 0g', 0 S' N
N
'N
[0466] LCMS (Method F, ES-API): RT 2.54 min, m+H 521.2; 111 NMR (400 MHz, CDC13): 8 8.05 (1H, d, J = 3.1 Hz), 7.74-7.71 (2H, m), 7.67 (1H, d, J = 3.1 Hz), 7.59-7.55 (1H, m), 7.51-7.47 (2H, m), 7.45-7.40 (2H, m), 7.29 (1H, s), 7.19-7.13 (211, m), 6.51 (1H, d, J = 2.5 Hz), 5.53 (1H, dd, J = 12.3,2.2 Hz), 4.22 (1H, d, J = 16.7 Hz), 3.91-3.85 (1H, m), 2.93-2.84 (2H, m), 2.70 (1H, d, J 12.4 Hz), 2.53-2.43 (2H, m).
.. Example 12E. (R)-(64(3-chlorophenyl)sulfonv1)-1-(4-fluorophenv1)-4,4a,5,6,7,8-hexahvdro-I il-08 rAzolo13,4-4,1isoquinolin-J1a-v1)( thiazol-2-µ,Omethalione ,:s' N/ I iN 1110 ci [04671 I,CMS (Method F, ES-API): RT 2.71 min, m+H = 555.2; 1H NMR (400 MHz, CDC13): 8 8.05 (111, d, J = 3.2 Hz), 7.69-7.67 (211, m), 7.61-7.58 (111, m), 7.54-7.51 (111, m), 7.45-7.40 (3H, m), 7.30 (111, s), 7.20-7.14(21'!, m), 6.53 (1H, d, J = 2.5 Hz), 5.52 (1H, dd, J =
12.6, 1.5 Hz), 4.21 (111, d, J= 16.8 Hz), 3.91-3.87 (1H, in), 2.93-2.83 (2H, m), 2.78 (1H, d, J =
12.4 Hz), 2.58-2.52 (2H, m).
Example 12F. (R)-(1-(4-ifluaroplien v1)-6-(m-tolvlsulfonv1)-44a,5.6,7.8-hexahydro-111-pyrazolo13,4-glisocini nolia-4a-v1)(5-nlet It Ow:xi n-2-vbniet hanone µSi`
Ns I ) N
[04681 LCMS (Method F, ES-API): KT 2.77 min, = 543.2; 1H NMR (400 MHz, CDC13): 8 8.46 (1H, m), 7.82 (111, d, J = 8.0 Hz), 7.61 (1H, ddd, :I= 8.0, 2.3, 0.9 Hz), 7.51-7.48 (2H, m), 7.45-7.40 (211, m), 7.35-7.33 (2H, m), 7.27 (1H, s), 7.18-7.12 (211, m), 6.46 (1H, d, ;1=
2.1 Hz), 5.57 (1H, dd, J = 112, 2.1 Hz), 4.29(111, d, J = 16.9 Hi), 3.84-3.79 (1H, m), 2.90-2.78 (2H, m), 2.70 (1H, d, J = 12.0 Hz), 2.48-2.39 (8H, m).
Example 12G. (R)-(1.-(4-fhoronhenv1)-6-(m-tolvlsulfonv1)-4,4a.5,6.7,8-hexa vti ro-1 pyrazo1o13,4-e1isoci ainalia-4a-y1)(4-methy Ipv ridin-2-v1)metha none .0 0 p N,1 I I
[04691 LCMS (Method F, ES-API): RT 2.75 min, m+H = 543.2; 1H NMR (400 MHz, CDC13): 6 8.50 (1H, dd, J =3.9, 0.4 Hz), 7.71 (1H, m), 7.51-7.48 (2H, m), 7.45-7.40 (2H, m), 7.35-7.33 (2H, m), 7.28-7.26 (2H, m), 7.18-7.12 (2H, m), 6.46 (1H, d, J = 2.1 Hz), 5.53 (1H, dd, J = 12.2, 2.1 Hz), 4.30 (1H, d, J = 16.9 Hz), 3.84-3.80 (1H, m), 2.90-2.77 (2H, m), 2.69 (1H, d, J
= 12.3 Hz), 2.48-2.42 (2H, m), 2.40 (3H, s), 2.39 (3H, s).
Example 1211. (R)-(1-(4-fluorophenvb-6-(m-tolvlsulfonv1)-4.4a,5,6,7,8-hexahydro-111-pvrazolo[3,4-glisoquinolia-4a-y1)(6-methylpyridin-2-yHmethanone = N µ?
N
N:
co, [0470i LCMS (Method F, ES-API): RI 2.77 min. m-1-11 = 543.0; 1H NMR (400 MHz, CDC13): 6 7.72 - 7.68 (2H, m), 7.42 - 7.36 (4H, m), 7.34- 7.30 (4H, m), 7.18 -7.13 (2H, m), 6.45 (11, d, J = 2.0 Hz), 5.55 (1H, dd, J = 12.2, 2.0 Hz), 4.19 (1H, d. J =
17.0 Hz), 3.84- 3.80 (1H, m), 2.87 (1H, d, J= 17.0 Hz), 2.83 - 2.73 (1 H:, m), 2.71 (1H, d, J =
12.2 Hz), 2.62 (3H, s), 2.54 - 2.42 (2H, m), 2.39 (3H, s).
Example 121.(11)46-(N-fluor -3-(trifluaromeiltyl)nheav1)sulfanv1)-1-(4-fluoronhenv11-4,4a,5,6,7õ8-hexakvdro-1H-pyrato1o13.4-alisoaainolin-4a-v1)(thiazol-2-vl)methanone r %IT

N
111" F
IJ
[04711 LCMS (Method F, ES-API): RT 2.77 min, m+H = 606.9; I H NMR (400 MHz, CDCI3): 8 8.00(111, d, J = 3.0 Hz), 7.98 (III, dd, J = 6.4, 2.3 Hz), 7.90 (I
II, ddd, J = 8.5, 4.3, 2.3 Hz), 7.68 (1H, d, J = 3.1 Hz), 7.47- 7.40(2H. m), 7.29 (1H, s), 7.27 - 7.25 (iH, m), 7.20 - 7.14 (2H, m), 6.55 (1H, d, J = 2.1 Hz), 5.49 (1H, dd, = 12.5, 2.1 Hz), 4.18 (IH, d, .1= 16.8 Hz), 3.94 (I H, ddd, J = 8.9, 5.1, 2.1 Hz), 2.93- 2.84(3H, m), 2.66- 2.55 (2H, m).
Example 12J. (R)-(1-(4-fluorophenv1)-6-((3,4.5-tri lloorophertths ifonv1)-4.4a,5.6.7,8-hexahvdro-11-1-ovrazolol3A-elisouninoli n-4a-y 1)(th Oct ha nom:
(11 s 0õ0 F
N I ' '1\1 411, .. [04721 LCMS (Method F, ES-API): RT 2.75 mm, m+H = 575.1; 1H NMR (400 MHz, CDC13): 8 8.04 (IH, d, J = 3.0 Hz), 7.70 (I H, d, J = 3.0 Hz), 7.47-7.41 (2H, m), 7.37-7.34 (2H, m), 7.30 (IH, s..), 7.20-7.14 (2H, m), 6.55 (I H, d, J = 2.1 Hz), 5.49 (1H, dd, J = 12.5, 2.0 Hz), 4.20 (111, d, .1= 16.8 Hz), 3.93-3.88 (1H, m), 2.92-2.83 (3H, m), 2.67-2.55 (2H, m).
Example I2K. (R)-(6-(0-fluoro-4-(trifluoromethvl)phenvlisulfonv1)-144-fluorophenv1)-1 5 4,4a.5,6.7,8-Itexahydro-M-pyrazolol3,4-141isoqui gmlill-4a-y1)(thiazol-2-yl)methanorie (I'll S'-'`-r () µ F:S53 ----".----''N- .' 40 N lj 'N ^=-..-1-":',..--"i r;--\ /
1....
F
[04731 LCMS (Method F, ES-API): RT 2.94 min, m+H = 607.1; I H NMR (400 MHz, CDCI3): 8 8.02 (111, d, J = 3.0 Hz), 7.73-7.69 (1H, m), 7.68 (III, d, J = 3.0 Hz), 7.59 (IFI, br d, J
= 8.2 Hz), 7.53 (III, br d, J = 9.4 Hz), 7.45-7.40(211, m), 7.30 (1E1, s), 7.20-7.14 (211, m), 6.55 (1H, d, J = 2.2 Hz), 5.52 (111, dd, j = 12.4,2.0 Hz), 4.20 (1H, d, J = 16.9 Hz), 3.96-3.92 (1H, m), 2.93-2.84 (31I, m), 2.67-2.62 (1H, m), 2.59-2.55(111, m).
Example IN.. (R)-(1-(4-11norophenv1)-6-43-(trilluoromeths Oplienxl)sillfoo v1)-4,4a,5,6,7,8-hexah.vd ro-1 11-p µ. razolo13.4-141 i sof.] uktoll n-4a-y1)(5-mettiv It II i azol-2-0) met h a n one ---S
W-Ily 9,.0 N...S' 00 CF3 I\I:' 1 ".
*
F
104741 LCMS (Method F, ES-API): RT 2.83 min, m+H = 603; 1H NMR (400 MHz, CDC13): 6 7.98 (I H, s), 7.91 (IH, br. d, J = 7.9 Hi), 7.84- 7.80 (1H, m), 7.68- 7.61 (2H, m), 7.46 - 7.39 (2H, m), 7.29 (1H, s), 7.20 -7.12 (2H, m),6.51 (1H, d, J = 2.1 Hz), 5.54 (1H, dd, J= 12.4, 2.1 Hz), 4.17 (1H, d, J = 16.7 Hz), 3.93 - 3.89 (1H, in), 2.95- 2.77 (3H, m), 2.60-2.49 (5H, m).
Example 12M. (R)-(1-(4-fluoropheny1)-6((3-(ttifluoromet h vl =iphenvI)sulfonv1)-4,4a.5.6.7,8-llexahydro-1H-pyrazolo13.4-glisoguinolin-4a-v1)(4-rnethylthiazol-2-vInnethanone l' i i N 0õ0 \ Si N CF, N Si =
I
104751 LCMS (Method F, ES-API): RT 2.80 min, m+H = 603.0; 1H NMR (400 MHz, CDCI3): 67.96 (IH, s), 7.88 (IH, d, j - 7.9 Hz), 7.80 (1H, d, J- 7.9 Hz), 7.62 (1H, t, J - 7.9 Hz), 7.42 (2H, ddt, J = 8.1, 5.6, 2.8 Hz), 7.30 (1H, s), 7.21 (1H, d, J = 0.9 Hz), 7.20 - 7.12 (2H, m), 6.52 (1H, d, j = 2.2 Hz), 5.56 (1H, dd,i = 12.4, 2.2 Hz), 4.18 (1H, d, J =
16.8 Hz), 3.95 -3.88 (1H, m), 2.91 - 2.80 (3H, m), 2.63 - 2.50 (5H, m).
Example 12N. (R)-(64(3,4-dichlorophenyl)sulfony11-1-(4-fluoro)henv1)-4,4a.5,6,7.8-hexahvdro-IH-pvrazolo13A-glisoquinolin-4a-y1)(thiazo1-2-vIlmethanone µs ,S diti N N I
(..1 çD
[04761 I,CMS (Method F, ES-API): RT 3.34 min, - 589.1; liINMR. (400 MHz, CDCI3): 6 8.00 (IH, d, J = 3.0 Hz), 7.77(111, dd, J = 1.8, 0.9 Hz), 7.67 (III, d, .1= 3.0 Hz), 7.54-7.48 (2H, m), 7.45-7.40 (211, m), 7.29 (111, s), 7.20-7.14(21:1, m), 6.54 (1I1, d, J = 2.1 Hz), 5.46 (I H., dd. J = 12.6, 2.0 Hz), 4.18 (IH, d, J = 16.9 Hz), 3.94-3.90 (Ili, m), 2.92-2.84 (3H. m), 2.66-2.54 (211, rn).
Example 120. (R)-(64(3,4-diehloropheavbsulfonv1)-1-(4-fluorophenv1)-4,4a,5,6.7.8-hexithydro.-111-pyrozolo13.4-21isoquenolin-4a-v1)(5-methvithiazol-2-vlimetltatione CI
N/ I N
CI
[04771 LCMS (Method F, ES-API): RT 2.92 min, m+II = 603.9; 1H NMR (400 MHz, CDC13): 6 7.77 (1H, d, J = 1.9 Hz), 7.60 (1H, d, J = 1.0 Hz), 7.56 - 7.48 (211, m), 7.45 - 7.40 (2H, m), 7.28 (1H, s), 7.21 -7.13 (211, m), 6.53 (1H, d, J = 2.1 Hz), 5.45 (1H, dd. J = 12.5, 2.1 Hz), 4.13 (1H, d, J = 16.6 Hz), 3.94(111, ddt, J = 8.5, 3.9, 2.0 Hz), 2.93 -2.84 (3H, m), 2.68 -2.61 (111, m), 2.57 (3H, d, J = 1.0 Hz), 2.58 - 2.52 (111, m).
Example 12P. (R)-(6-((3,4-difluorophenvl)sulfonv11-1-(4-fluorop hen vi--1,4a.5,6.7,8-hexahydro-114-nvrazoloPA-glisaa uinoli ii-4a-v1)(thiazol-2-v1)methanotte 0 y *
104781 LCMS (Method F, ES-API): RT 2.62 mm, m+H = 556.9; 111 'MAR (400 MHz, CDC13): 6 8.02 (1H, d, J = 3.1 Hz), 7.68 (1H, d, J = 3.1 Hz), 7.55-7.47 (211, m), 7.45-7.40 (2H, m), 7.29(111, s), 7.27-7.21 (111, m), 7.20-7.13 (2H, m), 6.54 (1H, d, J = 2.2 Hz), 5.47 (1H, dd, J
= 12.4, 2.0 Hi), 4.19(111, d, J = 16.8 Hz), 3.93-3.86(111, m), 2.93-2.79 (3H, m), 2.63-2.52 (2H, m).
Example 12Q. (R)464(3.4-difluoroplien 1)sti IfonvI)-1-(4-fluoropheny1)-4,4a,5,6.7,8-tx alivd ro- 11-1-pyrazolol3A-g1 isog pal noli 11-4a-s 1)(5-methylthiazol-2-0)meth a none 0 0õ0 NS/ F
Ni I =
IP' [04791 L.CMS (Method F, ES-API): RT 2.67 min, m+11 = 571.1; 1H NMR (400 MHz, CDC13): 6 7.63 (1H, m), 7.54-7.49 (211, m), 7.45-7.40 (211, m), 7.29 (Iii, s), 7.27-7.21 (1FI, m), 7.19-7.13 (2H, m), 6.52 (1H, d, J = 2.0 Hz), 5.44 (1H, dd, J = 12.4, 2.0 Hz), 4.15 (1H, d,1 = 16.9 Hz), 3.93-3.89 (111, m), 2.91-2.80 (311, m), 2.64-2.52 (5H, m).
Example 12R. (R)-(6-44-chloro-3-fluorouheavi)sulfonv1)-1 -(4-fluoronhenvI)-4,4a,5,6,7.8-hexa hvd ro-111-uvrazolo13 A-elisoa ulna I)(5-meihy Ithiazol-2-0)met ha n one N3fJN CI
104801 Using tetrahydroftran as the reaction solvent in place of diethyl ether. LCMS (Method F, ES-API): RI' 2.78 min, m+H = 587.1; 111 NMR (400 MHz, CDC13): 6 7.62 (1H, in), 7.50-7.40 (5H, m), 7.28 (1H, s), 7.19-7.13 (2H, m), 6.52 (1H, d, J = 2.0 Hz), 5.45 (1H, dd, J = 12.4, 2.0 Hz), 4.14 (1H, d, J = 16.9 Hz), 3.94-3.90 (1H, m), 2.91-2.82 (3H, in), 2.67-2.53 (5H, m).
Example 12S. (R)-(1-(4-fluorophenv1)-64(1-methvI-1111-pvrazol-3-v1)sulfonv1)-4.4a,5,6.7.8-htexalivdro-111-pvrazolo13.4-glisotininolin-4a-v1)(5-methylthiatol-2-v1)methanone fkr µ.µe 11/41"
N
N-N
[04811 1.,CMS (Method F, ES-API): RT 2.27 min, m+11 = 539.2; 1H NMR (400 MHz, CDC13): 6 7.71 (111, m), 7.46-7.41 (211., m), 7.39(111, d, J = 2.3 Hz), 7.30(111, s), 7,19-7.13 (2H, m), 6.60 (1H, d, J = 2.3 Hz), 6.52 (1H, d, J = 2.0 Hz), 5.59 (I H, dd, J
= 12.5, 1.9 Hz), 4.22 (1H, d, J = 16.9 Hz), 3.96 (3H, s), 3.92-3.88 (I H, m), 2.94-2.86 (3H, m), 2.69-2.62 (1H, m), 2.55 (3H, d, J = 0.9 Hz), 2.52-2.48 (1H, m).
Example 12T. (R)-(1-(4-fltiorookenv1)-64(1-metliv1-1H-pyrazol-4-v1)su1fonv1)-4,4a,53.6,7,8-hexahydro-111-nvrazolo 3.4-el isoguinolin-4a-v1)(5-rneth vi dhia fol-2-v nmethanone -0 Cp N47-1 , N-I
104821 LCMS (Method F, ES-AP1): RT 2.25 min, m+H 539.0; 1H N MR (400 MHz, CDC13): 6 7.72 - 7.65 (3H, m), 7.43 (2H, ddt, J= 8.2, 5.6, 2.8 Hz), 7.30(111, s), 7.20- 7.13 (2H, m), 6.51 (1H, d, J - 2.0 Hz), 5.48 (1H, dcl, - 12.1, 2.0 Hz), 4.19 (1H, d, J
.16.7 Hz), 3.93 (3H, s), 3.84- 3.79 (1H, m), 2.95- 2.83 (2H, m), 2.68 (1H, d, J = 12.1 Hz), 2.56 -2.43 (5H, m).
Example 121. (R)-(6-(( 1,3-di methyl- 111-nvrazol-5-vlisulfonv1)-1-(4-fluoropheny1)-4,4a.5,6,7,8-hexahvd ro- 111-pyrazolol 3,4-g isoquinolin-4a-y1)(5-methylthiazo1-2-µ 1)methanone ,0 0 0 ""r=-='-\ _______________________________________ N,N ...õ) N
[04831 Using tetrahydrofuran as the reaction solvent in place of diethyl ether. LCMS (Method F, ES-API): RI 2.46 min, m+H = 553.2; III NMR (400 MHz, CDC13): 8 7.61-7.60 (1H, m), 7.46-7.41 (2H, m), 7.29 (1H, s), 7.20-7.14(2F1, m), 6.55 (1H, d, J = 2.0 HZ), 6.46 (1H, s), 5.42 (1H, dd, .1= 12.5, 2.0 Hz), 4.20 (1H, d, J = 16.9 Hz), 3.96-3.92 (1H, m), 3.84 (3H, s), 3.01 (1H, d, J = 12.7 Hz), 2.92-2.76 (3H, m), 2.61-2.56 (4H, pi), 2.20 (3H, s).
Example 12V. (R)-(144-fluorophenv1)-64(1-methvl-lif-ovrazol-5-vbsulfonv1)-4,4a,5,6,7,8-hexahvdro-1H-ovrazolor3A-elisoauinolin-4a-v1)(5-methvIthiazol-2-v1)methanoae 0õ0 NI/ ) 104841 LCMS (Method F, ES-AP1): RT 2.40 min, m+H = 539.2; 1H N MR (400 MHz, CDC13): 8 7.61 (1H, m), 7.46-7.41 (2H, m), 7.35 (1H, d, J ¨ 2.0 Hz), 7.29 (1H, s), 7.20-7.14 (2H, m), 6.68 (1H, d, J = 2.0 Hz), 6.55 (114, d, J¨ 1.9 Hz), 5.45 dd, J= 12.5, 2.0 Hz), 4..20 (1H, d, J = 16.9 Hz), 3.97-3.93 (4H, m), 3.02 (1H, d, J = 12.7 Hz), 2.92-2.76 (3H, m), 2.61-2.55 (4H, m).
Example 12W. (R)-(6-((1-ethy1-1H-pyrazol-5¨vi)sulfonv1)-1-(41-11uorophenv1)-4,4a,5,6.7.8-hexa Ilvdro-1H-pvrazolp[3.4-0soquino1in-4a-v1)(th iazo1-2-vOrnetha none oõ.
N,Ni (Nu 104851 LCMS (Method F, ES-API): RT 2.40 min, m+H = 539.1; 1H NMR (400 MHz, CDC13): 8 7.98 (1H, d, J = 3.1 Hz), 7.65 (1H, d, J = 3.1 Hz), 7.47-7.41 (2H, m), 7.39 (1H, d, J =
2.0 Hz), 7.30 (1H, s), 7.20-7.14 (2H, m), 6.64 (1H, d, J = 2.0 Hz), 6.57 (1H, d, J = 1.8 Hz), 5.48 (1H, dd, J = 12.7, 2.1 Hz), 4.33-4.16 (3H, m), 3.96-3.91 (1H, m), 3.04 (1H, d, J = 12.7 Hz), 2.92-2.77 (3H, m), 2.62-2.58 (1H, m), 1.40 (3H, t, J = 7.2 Hz).
Example 12X. (R)-(64(1-ethyl-1H-pvrazol¨l-v1)sulfonv1)-1-(4-fluorophenv1)-4,4a,5.6,7.8-hexahydro-1H-pvrazolof 3.4-glisoattinolin-4a-y1)(thiazol-2-y1)met ha none N' NI IN
N
104861 LCMS (Method F, ES-API): RT 2.24 min, m+H = 539.1; 1H NMR (400 MHz, CDC13): 8 8.06 (1H, d, J= 3.1 Hz), 7.73 (1H, s), 7.68-7.67 (2H, m), 7.46-7.41 (2H, m), 7.31 (1H, 0, 7.20-7.14 (2H, m), 6.53 (1H, d, J = 2.2 Hz), 5.49 (1H, dd, J = 12.2, 2.0 Hz), 4.23 (1H, d, J = 16.9 Hz), 4.19(2H, q, J= 7.3 Hz), 3.85-3.80(1H, m), 2.95-2.86(2H, m), 2.70 (1H, d, J=
12.2 Hz), 2.55-2.44 (2H, m), 1.52 (3H, t, J = 7.3 Hz).
Example 12Y. (12)-(1-(4-fluoropheny1)-640-Qropv1-111-pyrazol-4-v1)sulfony1)-4.4a,5,6õ7,8-hexahvdro-111-Dvrazolo13.4-glisoquinolin-4a-y1)(thiazol-2-y1)methanone /I'S

/7 3 N: --- - N ''-'r N ! 1 %
'NI ---' ---- *--= N' \
( /
F
104871 LCMS (Method F, ES-API): RT 2.45 min, m+H = 553; 111. NMR (400 MHz, CDC13): 6 8.07 (d, 3= 3.1 Hz, I H), 7.72 (d, J = 0.7 Hz, 1H), 7.70 - 7.65 (in, 2H), 7.49 - 7.39 (m, 2H), 7.31 (s, 1H), 7.22 -7.11 (m, 2H), 6.54 (d, J = 2.3 Hz, 1H), 5.50 (dd, J = 12.1, 2.1 Hz, 1H), 4.23 (d, J =
16.8 Hz, 1H), 4.09 (t, J = 7.1 Hz, 2H), 3.87 -3.78 (m, 1H), 2.97 - 2.84(m, 2H), 2.68 (d, J = 12.2 Hz, 1H), 2.57 - 2.39 (m, 2H), 1.91 (sext., J = 7.3 Hz, 211), 0.92 (t, J = 7.4 Hz, 3H).
Example 12Z.
i (R)-(1-(4-fluoropheny1)-6- 1 el ((2-methy1-2H-1,2,3-triazol- I N''''. .s..- (a: 0 4-ypsulfony1)-4,4a,5,6,7,8- I /i------,----'1, '-''''N's':::" r-N=fq-Isomer hexahydro- I H- 1 Nsrµi I 1 ,) A pyrazolo[3,4-disoquinolin- 1 4a-y1)(thiazol-2- ..-ypmetharione \ 4.
F , (R)-(1-(4-fluorophenyI)-6- e--((1- methyl-1 H-1,2,3-triazol- N- 0 0õ0 /
5-yOsulfony1)-4,4a,5,6,7,8- /
Isomer hexahydro- I H- N
'N N
B mazolo[3,4-disoquinolin-4a-y1)(thiazol-2-yl)methanone . F

eS (R)-(1-(4-fluoropheny1)-6-((1-methyl- 1 II-1,2,3-triazol-1 4-yDsulfony1)-4,4a,5,6,7,8- / N
Isomer hexahydro-1H- N I N 0,N
C pyrazolo[3,4-g]isoquinolin-4a-y1)(thiazol-2-yl)methanone F
104881 Prepared from Intcrmcdiatc 94. LCMS (Method F, ES-API): RT 2.26 min, m+H
526.1; 1H NMR (400 MHz, CDC13): 6 8.07 (1H, d, J = 3.1 Hz), 7.81 (11, s), 7.67 (1H, d, J = 3.1 Hz), 7.47-7.42 (2H, m), 7.31 (1H, s), 7.20-7.14 (2H, m), 6.56 (1H, d, J = 2.1 Hz), 5.63 (1H, dd, J
= 12.6. 2.1 Hz), 4.25 (3H. s), 4.24 (1H, d, J = 16.9 Hz), 3.97-3.93 (1H, m), 2.99 (1H, d. J = 12.7 Hz), 2.99-2.86 (2H, m), 2.77-2.70 (1H, m), 2.57-2.52 (1H, m).
Example 12AA.
(R)-(1-(4-fluoropheny1)-6-(---8 0 0 ((2-propy1-2H-1,2,3-triazol- N
4-yl)sulforty1)-4,4a,5,6,7,8- ..N
Isomer hexahydro-1H- N,N
N
A pyrazolo[3,4-g]isoquinolin-4a-y1)(thiazol-2-yl)methanone (R)-(1-(4-fluorophenyI)-6- rs 01-propy1-1H-1,2,3-triazol- N
5-yl)sulfony1)-4,4a,5,6,7,8- , Isomer hexahydro-1H- N, B pyrazolo[3,4-g]isoquinolin-4a-y1)(thiazo1-2-yOmethanone (R)-(1-(4-fluoropheny1)-6-(1-propy1-1H-1,2,3-triazo I- N0- ,$) 4-yl)sulfony1)-4,4a,5,6,7,8- N
Isomer hexahydro-1H- N
`"N
C pyrazolo[3,4-g]isoquinolin-4a-y1)(thiazol-2-yOmethanone 104891 Prcparcd from Intermcdiatc 95. LCMS (Mcthod F, ES-API): RT 2.54 min, m+H
554.2; 1H NMR (400 MHz, CDCI3): 6 8.08 (1H, d, J = 3.1 Hi), 7.82 (11, s), 7.68 (1H, d, J = 3.1 Hz), 7.47-7.42 (2H, m), 7.31 (1H, s), 7.20-7.14 (2H, m), 6.55 (1H, d, J = 2.2 Hz), 5.64 (1H, dd, J
= 12.6. 2.0 Hz). 4.43 (2H. t J = 7.1 Hz). 4.25 (1H, d, J= 16.9 Hz). 3.97-3.92 (1H. m). 2.96 (1H.
d, J = 12.9 Hz), 2.94-2.86 (2H, m), 2.74-2.67 (1H, m), 2.56-2.52 (1H, m), 2.01 (2H, sext, J = 7.1 Hz), 0.94 (3H, t, J = 7.1 Hz).
Example 13. (R)-(144-fluorophenv11-6-tosyl-4,4a,5,6.7,8-hexahydro-1H-pyrazo1o13,4-gliSOalliflOhn-4a-vb(1-methyl-1H-imidazol-2-v1)methanooe rNz it .0 N,/ I
[04901 1-Methyl-1H-imidazole (104 mg, 1.267 mrnol) in dry ether (5 mL) was added to butyllithium (2.5M in hexartes) (519 ti, 1.298 mmol) in dry ether (2 ml.,) at -78 'C. The reaction mixture was stirred at -78 C for 45 minutes. A. solution of (R)-methyl 1.-(4-fluoropheny1)-6-tosyl-4,4a,5,6,7,8-hexahydro-1.H-pyrazolo[3,4-disoquinoline-4a-carboxylate (200 mg, 0.415 minol) in dry ether (5 rnI-) was added dropwise and the reaction mixture was stirred for 45 minutes at -78 C, then allowed to warm to room. temperature over 2 hours.
Water (20 mL) was added and the reaction mixture was stirred at room temperature for 10 minutes.
The aqueous phase was extracted with ethyl acetate (3 x 20 mL), the combined organic phases were washed with brine (20 mL), dried (magnesium sulfate), and solvent removed to give a yellow oil. The crude product was purified by chromatography on silica gel (gradient: 0-60%
ethyl acetate in isohexane) to afford (R)-(1-(4-fluoropheny1)-6-tosyl-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-g]isoquinolin-4a-y1)(1-methyl-1H-imidazol-2-yl)methanone (22 mg) as a pale yellow solid.
LCMS (Method F, ES-API): RT 2.52 min, m+H = 532.0; 1H NMR (400 MHz, CDCI3): 8 7.61 -7.58 (2H, m), 7.46 - 7.40 (2H, in), 7.31 (1H, s), 7.29 - 7.27 (2H, m), 7.18 (1H, d, J = 0.9 Hz), 7.17 - 7.12 (2H, m), 6.99 (1H, hr. s), 6.50 (1H, d, J = 2.2 Hz), 5.53 (1H, dd, J = 12.2, 2.2 Hz), 4.45 (1H, d, J= 16.7 Hz), 3.88 - 3.84 (4H, m), 2.92 - 2.78 (2H, m), 2.60 (1H, d, J = 12.2 Hz), 2.50 - 2.37 (511, m).
10491] The following examples were similarly prepared from the appropriate starting materials:
Example 13A.111)-(1-(4-fluoropheny1)-6-(m-tolvisu1fonv1)74µ4a,5,6.7,8-hexahvdro-1H-pvrazolo13,4-glisoquinalin-4a-v1)(1-methyl-111-imidazal-2-y1)methanone Cz N
N I
\
[0492] LCMS (Method F, ES-API): RT 2.52 min, m+H = 532.2; 1H NMR (400 MHz, CDCI3): 8 7.52-7.49 (2H, m), 7.46-7.36 (4H, m), 7.32 (1H, s), 7.20 (1H, d. J =
0.9 Hz), 7.18-7.12 (2H, rn), 7.00 (1H, d, J= 0.4 Hz), 6.51 (1H, d, J = 2.2 Hz), 5.55 (1H, dd, J = 12.2, 2.1 Hz), 4.46 (1H, d, J = 16.7 Hz), 3.89-3.85 (4H, m), 2.91-2.80 (2H, m), 2.62 (1H, d, J = 12.4 Hz), 2.51-2.40 (5H, rn).
Example 14. (R)-34(1-(4-fluorophenv1)-4a-pieolinov1-4a.5,7,8-tetrahydro-1H-Dvrazolo13,4-glisoquinolin-6(4H)-v1)sulfoity1)-N,N-di met It awn/amide ====. 40 0, IS
Isk I N

[04931 2-(1H-7-Azabenzotriazol-1-y1)--1,1,3,3-tetramethyl uronium hexafluorophosphate Methanaminium (HATLT) (42.7 mg, 0.112 nunol) was added to a solution of (R)-3-((1-(4-fluoropheny1)-4a-picolinoy1-4a,5,7,8-tetrahydro-IH-pyrazolo[3,4-g]isoquinolin-6(4H)-ypsulfonyl)benzoic acid (57 mg, 0.102 mmol), dimethylamine (51.0 p1, 0.102 intnol) and triethylamine (28.4 pi, 0.204 mmol) in dichloromethane (3 mi..). The resultant mixture was stirred at room temperature for 1 hour. The reaction was diluted with dichloromethane (5 ml.,) and washed with a saturated solution of sodium hydrogen carbonate (aqueous, 5 ml.). The organic phase was passed through a phase separator and solvent removed to give a yellow solid.
The crude product was purified by chromatography on silica gel (gradient: 0-100% ethyl acetate in isohexane) to afford (R)-3-41-(4-fluorophenyl)-4a-pieolinoy1-4a,5,7,8-tetrahydro-111-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfony1)-N,N-dimethylbenzamide (7 mg) as a white solid.
LCMS (Method F. ES-API): RT 2.24 min, m+H = 586.1; 1H NMR (400 MHz, CDC13): 8 8.68 (1H, ddd, J = 4.7, 1.7, 0.9 Hz), 7.90(11-1, dt, J = 7.9, 1.2 Hz), 7.84 (1H, td, J =: 7.7, 1.7 Hz), 7.74 -7.71 (2H, m), 7.61 (1H, dt, J = 7.7, 1.4 Hz), 7.57 - 7.39 (4H, m), 7.28 (114, s), 7.20 - 7.13 (21-1, m), 6.47(111, U. J = 2.0 Hz), 5.52 (1H, dd,J = 12.1, 2.0 Hz), 4.27 (1H, d,1 16.9 Hz), 3.86 -3.77 (1H, m), 3.14 (31-1, s), 2.94 - 2.76 (5H, m), 2.70 (1H, d, J = 12.1 Hz), 2.50 - 2.43 (2H, m).
Example 15. (R)-(6-((1-ethvi-11-1-nvrazol-41-v1)sulfonv1)-1.-(4-fla o ronhenv1)-4.4a.5,6,7,8-\ vdro-1 1-1-11-razolol3A-21ismi uinoli 4a-A1)(4-(trifluoroniethy1)00..
ridin-2-N
N-NI, I I N
[0494] 2-Bromo-4-(trifluoromethyl)pyridine (171 1, 1.382 mm.ol) in dry tetrahydrofuran (1 mL) was added to butyllithium (2.5 M in tiexanes) (885 jil, 1.416 mmol) in dry tetrahydrofuran (2 mL) at -78 C. The reaction mixture was stirred at -78 C, for 45 minutes, then a solution of (R)-methyl 6-((l-ethy1-1H-pyrazol-4-yl)sulfony1)-144-fiuorophenyl.)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-disoquinoline-4a-carboxylate ( 220 mg, 0.453 mmol) in dry tetrahydrofuran (2 nit) was added dropwise and the reaction mixture stirred for 1 hour at -78 'C.
Water (10 mi..) was added and the reaction mixture was stirred at room temperature for 10 minutes. The aqueous phase was extracted with ethyl acetate (2 x 15 mL), and the combined organic layers were washed with brine (20 mi.), dried over magnesium sulfate, filtered and concentrated in vacuo to give an orange oil. The crude product was purified by chromatography on silica gel (gradient: 0-80% ethyl acetate in isohcxane) and preparative HPLC (Waters, Acidic (0.1%
Formic acid), Waters X-Sclect Prep-C18, 5 um, 19x50 mm column, 35-70% aectonitrile in water) to afford (R)-(6-((1-ethy1-1H-pyrazol-4-y1)sulfony1)- -(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-y1)(4-(trifluoromethApyriclin-2-yOmethanone (23 mg) as a white solid. LCMS (Method F, ES-API): RT 3.00 min, m+H = 601.2; 1H NMR (400 MHz, CDC13):
8.88-8.87 (1H, m), 8.15 (1H, m), 7.71-7.69 (2H, m), 7.67 (1H, d, J = 0.6 Hz), 7.47-7.42 (2H, m), 7.30 (1H, s), 7.20-7.14 (2H, m), 6.51 (1H, d, J = 2.0 Hz), 5.44 (1H, dd, J =
12.0, 2.0 Hz), 4.22-4.16 (3H, m), 3.80-3.76 (1H, m), 2.94 (1H, d, .1= 16.9 Hz), 2.88-2.79 (1H, m), 2.67 (1H, d, J =
12.3 Hi), 2.52-2.40 (2H, m), 1.51 (3H, t, i = 7.3 Hz).
104951 The following examples were similarly prepared from appropriate intermediates:
Example 15A. (11)-p.% ritlin-2-vi(HDvridin-3-1,-1)-6-(3-(trilluorometlivI)phenvI)sulfonvi)-4,4a,5.6,7,8-hexalli,dro-Hi-vvrazolo13,4-glisotininolin-.4a-vOrnethargone io c 104961 LCMS (Method F, ES-API): RT 2.33 mm, m+H = 566.0; 1H NMR (400 MHz, CDCI3): 6 8.78 - 8.76 (1H, m), 8.66 (1H, ddd, J = 4.7, 1.6, 0.9 Hz), 8.61 (111, dd, J = 4.7, 1.6 Hz), 7.94 (11-1. s), 7.90 - 7.79 (511, m), 7.62 (1.H, t, J = 7.9 Hz), 7.48 (111, ddd, J = 8.8, 6.2, 1.5 Hz), 7.44(111, ddd, J = 8.8, 4.8, 0.7 Hz), 7.36(111, s), 6.56 (1H, d, J =2.0 Hz), 5.57(111, dd, J =
12.3, 2.0 Hz), 4.30 (111, d, J= 17.0 Hz), 3.92 - 3.85 (I H, m), 2.93 - 2.78 (311, m), 2.62 - 2.50 (211, m).
Example I513, (R)-(6-(t3,4-dielliorophowl)sulfonvi)-1-piten0-4,4a3,6,7.8-hexalmirol 1-pyrazolo13,4-glisoottinotin¨Ia-v1)(pyridin-2-0)methanone -S*Li N
\
104971 Quenching the reaction with acetic acid in place of water. LCMS (Method F, ES-API):
RI 2.83 min, m-++1 = 565.0; 1H NMR (400 MHz, CDCI3): 8 8.62-8.60 (1H, m), 7.88-7.81 (2H, m), 7.74 (1H, dd, J = 1.8, 0.4 Hz), 7.52-7.44 (7H, m), 7.38-7.34 (1H, m), 7.29 (I H, 0, 6.57 (1H, d, J::: 2.1 Hz), 5.54 (1H, dd,J = 12.3, 1.9 Hz), 4.26 (1H, d, J = 16.8 Hz), 3.91-3.85 (IH, m), 2.92-2.75 (3H, m), 2.64-2.49 (2H, m).
Example 15C. (R)-(6-0,4-dichlaranhenvl)sulfonv11-1-(3,4-d int ol=ophen vh-4,4a.5,6,7,8-hexahvdro-IH-1)% razolol3A-211soauino1in-4a-v1)(pyridin-2-v1)M011a gl On e N
N I
N
CI
104981 Quenching the reaction with acetic acid in place of water. LCMS (Method F, ES-API):
RT 2.93 min, m+H = 600.9; 1H NMR (400 MHz, CDC13): 6 8.59 (1H, dt, J = 4.7, 1.4 Hz), 7.86 -7.79 (2H, m), 7.73 (1H, d, J= 1.9 Hz), 7.52- 7.43 (3H, m), 7.34 (1H, ddd, J =
10.7,6.9, 2.5 Hz), 7.29 7.24 (211, m), 7.22 - 7.18 (1H, m), 6.51 (1H, d, J = 2.2 Hz), 5.50 (1H, d, J = 12.5 Hz), 4.23 (1H, d, J = 16.9 Hz), 3.90 - 3.84 (111, m), 2.93 - 2.80(311, m), 2.64 (111, td, J = 11.7,3.4 Hz), 2.53 (1H, dt, J = 14.8, 2.3 Hz).
Example 15D. (11)-(64(3,5-difluoro-4-methoxvphenvI)sulfonyl)-1 o rop ell v1)-4,4a,5,6,7.8-hexahvdro-1H-pvi atolo[3,4-gi istmaiaolia4a-v1)(pv ith0-2-118k3V(1333tune 0 Ckp -==== F
N
OMe 104991 LCMS (Method F, ES-API): RT 2.65 min, m+H = 581.2; 1H NMR (400 MHz, DMSO-d6): .5 8.72 (1H, ddd, J = 4.7, 1.7, 0.9 Hz), 8.00(111, dt, J = 7.7, 1.7 Hz), 7.76 (1H, dt, 7.7,0.9 Hz), 7.66 (1H, ddd, J = 7.7,4.7, 1.2 Hz), 7.51-7.47 (2H, m), 7.44-7.42(2H, m), 7.40-7.36 (3H, m), 6.65 (111, s), 5.30(111, dd, J = 12.5, 1.7 Hz), 4.09 (1H, d, J = 16.9 Hz), 4.04 (3H, m), 3.75-3.73 (1H, m), 2.97-2.90 (2H, m), 2.64-2.54 (3H, m).
Example 16. (R)-(64(6-(dimethylamino)pyridin-3-v1)sulfony1)-144-fluorophenv1)-4,4a,5.6.7.8-hexahvdro-lH-pyrazoloilkglisoauinolin-la-y1)(tryridin-2-thmethanane 0õ0 ,s N
105001 (R)-(6-46-chloropyridin-3-yl)sulfonyD-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo[3,4-glisoquinolin-4a-y1)(pyridin-2-yl)methanone (30 mg, 0.055 mmol) was dissolved in a solution of dimethylamine in tetrahydrofuran (2M, 545 ftl, 1.091 mmol), and the reaction mixture stirred at room temperature overnight. The solvent was removed in vacuo to give a yellow oil, which was purified by chromatography on silica gel (gradient: 10-100% ethyl acetate in isohexane) to afford (R)-(646-(dimethylamino)pyridin-3-yl)sulfony1)-1-(4-fluoropheny1)-4,43,5,6,7,8-hexahydro-1H-pyrazolo[3,4-disoquinolin-4a-y1)(pyridin-2-yl)methanone (25 mg) as a pale yellow solid. LCMS (Method F, ES-API): RT 2.38 min, m+H = 559.3; 1H
NMR (400 MHz, CDC13): 6 8.62 (11, ddd, .1= 4.8, 1.8, 0.9 Hz), 8.43 (1H, d, J=2.5 Hz), 7.88 (1H, dt, J=
8.0, 1.1 Hz), 7.81 (1H, td, J= 7.7, 1.8 Hz), 7.60 (1H, dd, J = 9.1, 2.5 Hz), 7.46- 7.40(3H, m), 7.28 (1H, s), 7.20 -7.12 (21, m), 6.47 (1H, d. J = 2.2 Hz), 6.39 (1H, dd, J =
9.1, 0.8 Hz), 5.47 (1H, dd, J = 12.0, 2.2 Hz), 4.29 (1H, d, J = 16.9 Hz), 3.84 - 3.79 (1H, m), 3.14 (6H, s), 2.92 -2.75 (2H, m), 2.70 (1H, d, .1= 12.0 Hz). 2.51 -2.44 (2H, m).
Example 17. (R)-540-(4-fluoraphenv1)-4a-picolinoy1-42.5,7,8-tetr2h dra-1 fl-pvrazolo13,4-glisoquinolin-6(4H)-v1)sulfonv1)-1-methylDvridin-2(114)-one N I
[0501j 1-Methyl-6-oxo-1,6-dihydropyridine-3-sulfonic acid, ammonium salt (1 g, 4.85 mmol) was suspended in N,N-dimethylformamide (8 ml), and thionyl chloride (2.1 ml) was added. The reaction mixture was stirred at room temperature for 3 hours, giving a clear brown solution, before evaporation in vacuo to give crude sulphonyl chloride as a pale brown viscous oil. (R)-tert-butyl I -(4-fluoropheny1)-4a-picolinoy1-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate (0.2 g, 0.421 mmol) was dissolved in HC1 (4M in dioxane) (2.107 ml, 8.43 mmol), and the reaction mixture stirred at room temperature for 45 minutes, then evaporated to give a yellow solid. This intermediate was dissolved in dichloromethane (8 rriL) and triethylamine (1.175 ml, 8.43 mmol), and 25% of the crude sulphonyl chloride added. The reaction mixture was stirred at room temperature for 72 hours, then diluted with dichloromethane (100m1) and washed with 2M hydrochloric acid (2x50m1), and the organic phase dried (magnesium sulfate), filtered and evaporated to give a brown gum. The crude product was purified first by chromatography on silica gel (gradient: 50-100% ethyl acetate in isohexane), followed by preparative HPI,C (Gilson, Acidic (0.1% Formic acid), A gilent Prep C-18, 5 pm, 21.2x50 mm column, 25-40% acetonitrile in water) to afford (R)-5-((1-(4-fluoropheny1)-4a-picolinoy1-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-disoquinolin-6(4H)-yl)su1fony1)-methylpyridin-2(1H)-one (5 mg) as a white solid. I,CMS (Method F, ES-API): RT
2.08 min, m-4-H = 546.2; 1H NMR (400 MHz, CDC13): S 8.56 (1H, d, J = 3.3 Hz), 7.88-7.79 (3H, m), 7.50-7.40 (3H, m), 7.33(111, d, J= 9.2 Hz), 7.29-7.27 (1H, m), 7.17 (2H, t, J = 8.3 Hz), 6.52 (1H, s), 6.35 (1H, d, J = 9.6 Hz), 5.52(111, d, J = 12.5 Hz), 4.23 (111, d, J = 16.7 Hz), 3.91-3.84(111, m), 3.51 (3H, s), 3.02-2.70 (4H, m), 2.55 (1H, d, J = 14.4 Hz).
Ex:3ilwle 18. (R)-(1-(4-fluoronlienv1)-6-01-methyl-1H-p% rato1-4-vbsulfonv1)-401a.5,6,7,8-he\ Ahµd ro-111-pyrazolof3A-klisoquinolits-4a-v1)(4-(trifluoromethA)Dvridin-2-,, woctil n ogic , 00'0 N1 Ir,N
slq 1.05021 HCliDioxane (4M) (25.3 ml, 101 mmol) was added to (R)-tert-butyl 1-(4-fluorophcny1)-4a-(4-(trifluoromethyppicolinoy1)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-glisoquinoline-6(4H)-carboxylate (2.75 g, 5.07 mmol) and the reaction mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo to give an orange gum. This was dissolved in dichloromethane (75 mL) and Hunig's base (4.43 ml, 25.3 nunol) was added followed by 1-methyl-1H-pyrazole-4-sulfonyl chloride (1.099 g, 6.08 nu-nol).
The reaction .. mixture was stirred at room temperature for I h. The solvent was removed in vacuo to give an orange oil. The crude product was purified twice by chromatography on silica gel (gradient: 0-70% ethyl acetate in isohexane, followed by 0-60% ethyl acetate in dichloromethane), to give (R)-(1-(4-fluoropheny1)-6-((i -methyl-1H-pyrazol-4-yl)sulfony1)-4,4a,5,6,7,8-hexahydro- 1H-pyrazolo[3,4-g]isoquinolin-4a-y1)(4-(trifluoromethyl)pyridin-2-yOmethanone (1.89 g) as a pale yellow solid. I.CMS (Method F, ES-API): RT 2.39 min, m+H = 587.2.; 1H NMR (400 MHz, CDC13): 6 8.87 (1H, d, J = 5.0 Hz), 8.16-8.15 (1H, m), 7.72-7.70 (1H, m), 7.69-7.66 (2H, m), 7.47-7.42 (2H, m), 7.30 (1H, s), 7.21-7.14(2H, m), 6.51 (1H, d, J = 2.1 Hz), 5.44 (1H, dd, J =
12.0, 2.1 Hz), 4.21 (IH, d, J= 16.9 Hz), 3.93 (3H, s), 3.80-3.76 (1H, m), 2.94 (IH, J= 16.9 Hz), 2.88-2.79 (1H, m), 2.66 (1H, d, .1= 12.1 Hz), 2.53-2.48 (1H, m), 2.43 (1H, ddd, .1 = 12.6, 10.5, 3.5 Hz).
Example 19. (R)-(64(3.4-dieblorophenvI)sulfony1)-1-(4-fluorophenv1)-4,4a,5,6,7,8-hex ahydro-111-uvraz01013.4-21isopuinoli n-4a-v1)(thiazol-4-v1)methanone i C1 N

.--,,f/-----"*'s= '''..N- µNeN
N,N
I ¨
F
105031 To Fla 2M in ether (2809 pl, 5.62 mmol) was added (R)-tert-butyl 1-(4-fluorophenyI)-4a-(thiazole-4-carbonyl)-4a,5,7,8-tetrahydro-IH-pyrazolo[3,4-disoquinoline-6(44)-carboxylate (135 mg, 0.281 mmol) as a solution in ether (1 mL). The resulting suspension was stirred at room temperature for 1 h. The solvent was removed to give a white solid. This was dissolved in dichloromethane (1.4 mL) and Hunig's base (245 pl, 1.405 mmol), and 3,4-dichlorobenzene-1-sulfonyl chloride (76 mg, 0.309 mmol) was added to the solution. The resulting solution was stirred at room temperature for 18 h. The crude product was purified by chromatography on silica gel (gradient: 5-95% ethyl acetate in isohexane to afford (R)-(643,4-dichloro phe nyl)sulfony1)-1-(4-fluoropheny1)-4,4a,5,6,7,8-hexahydro-IH-pyrazolo [3,4-g]isoquinolin-4a-y1)(thiazol-4-yl)methanone (111 mg) as a pale yellow solid.
LCMS (Method F, ES-API): RT 2.76 min, m+H = 588.8; 1H NMR (400 Wiz, CDCI3): & 8.85 (1H, d, J =
2.2 Hz), .. 8.22 (1H, d, J = 2.2 Hz), 7.77 (1H, t, J = 1.2 Hz), 7.52 (2H, d, J = 1.2 Hz), 7.45- 7.40(2H, m), 7.28 (1H, s), 7.20 - 7.13 (2H, m), 6.52 (1H, d, J = 2.2 Hz), 5.44 (1H, dd, .1=
12.6, 2.2 Hz), 4.13 (111, d, J = 16.8 Hz), 3.90 - 3.87 (1H, m), 2.92 - 2.81 (2H, m), 2.78 (1H, d, 5= 12.6 Hz), 2.62 -2.50 (211, m).
Example 20. Glueocortieold Receptor (CR) Fluorescence Polarisation (FP) Binding Assay [05041 The following is a description of a FP assay for measuring compound inhibition of labelled glucocorticoid binding to the human recombinant OR.
[05051 The binding affinity of test compounds was determined using a FP
binding assay using human recombinant GR (PanVera P2812) and a fluorescent labelled glucocorticoid ligand (Fluorome GS Red) (PanVera P2894). The presence of inhibitors prevents the formation of a GS
ReclIGR complex resulting in a decrease in the measured polarisation value.
The change in polarisation value in the presence of test compounds is used to calculate the binding affinity of the compound for OR.
[0506] This assay was performed in 384 well, black, round-bottom, polypropylene micro titre .. plates in a final volume of 20p.I. The assay contained 5p1 InM OR (final concentration), 5p.1 0.5nM Fluorome GS Red (final concentration) in the presence of 10p.1 test compounds. Positive control wells (high polarisation) receive, 101.t1 2% (v:v) DMSO vehicle (1%
(v/v) final concentration) + 5 I I nM OR and 5 1 0.5nM Fluororne GS Red. Negative control wells (low polarisation) receive 10p.1 21IM dexamethasone (I AM final concentration) +
5ji1 inM OR and .. 5p,1 0.5nM Fluorom.e GS Red. Assay blank background wells (used for normalisation) receive 150 lx GS screening 'buffer + 511.1 GR.
[05071 For the IC50 determination (concentration of compound that displaces 50% of the bound OS Red), compounds were tested at eight different concentrations in duplicate in two independently performed experiments. Compounds were prepared as solubilised solids at iOniM

in DMSO. On the day of assay, an 8 point half-log serial dilution (55g1 DMSO +
25g1 compound solution) was prepared. A 1:50 dilution (10 compound solution + 49g1 lx GR
screening buffer) was prepared for each compound. The compounds were prepared at 2x final assay concentration.
105081 The reagents were added to the 384 well micro titre plates in the following order: 101.11 test compound/vehicle/1AM dexamethasone, 51j1Fluorome GS Red and 51.1.1 OR.
The plates were mixed and incubated for 4 hour at room temperature. FP was measured using an Envision Excite plate reader with 535 nm excitation and 590 nm emission interference filters.
105091 Milli-polarisation (m13) values were calculated using the below equation:
mP = 1000 * (S-G*P) / (S+G*P) where S and P are assay blank background subtracted fluorescence units, G¨ G-factor (1.07).
105101 Compound 1050 values were calculated by plotting a [compound] v. %
inhibition curve and fitting the data to a 4-parameter logistic fit equation. Compound KJ
(equilibrium dissociation constant) values were determined from the experimental IC50 values using a ligand depletion correction equation (see below) assuming the antagonists were competitive inhibitors with respect to dexamethasone (Pharmacologic Analysis of Drug Receptor Interactions, rd Ed., p385-410, 1993, Raven Press, New York).
= (Lb)*(1Cso)* (d) (L0)*(R0) + Lb*(R0 - L0+ Lb - Kd) Equilibrium dissociation constant of GS red ligand (Kd) 0.3riM
Bound tracer concentration (Lb) 0.3nM
Total tracer concentration (L0) 0.5nM
Total receptor concentration (Ro) I .0nM
Reagents:
105111 10x GR screening buffer (100mM potassium phosphate pH 7.4, 200mM
Na2M004, imM EDTA, 20% (v/v) DMSO). To prepare Ix OR screening buffer, combine I ml 10x OR
screening buffer (PanVera P2814) -1- .1 ml stabilising peptide (PanVera P2815) + 7.95m1 4 C MQ
water. Add 50g11M DTT, vortex and place on ice until use.
Example 21. ElepG2 Tyrosine Aminotransferase (TAT) Assay [0512] Glucocortieoid mediated activation of TAT occurs by transactivation of glucocorticoid response elements in the TAT promoter by glucoeorticoid receptor¨agonist complex. The following protocol describes an assay for measuring induction of TAT by dexamethasone in HepG2 cells (a human liver hepatocellular carcinoma cell line; ECACC, UK).
[0513] TAT activity was measured as outlined in the literature by A. Ali et al., J. Med. Chem., 2004, 47, 2441-2452. Dexamethasone induced TAT production with an average EC50 value (half-maximal effect) of 20nM.
[0514] HepG2 cells were cultured using MEME media supplemented with 10% (v/v) foetal bovine serum; 2n-iM L-glutamine and 1% (v/v) NEAA at 37 C, 5%/95% (v/v) CO2/air. The HepG2 cells were counted and adjusted to yield a density of 0.125 x 106 cells/rrd in RPMI 1640 without phenol red, 10% (v/v) charcoal stripped FBS, 2mM L-glutamine and seeded at 25,000 cells/well in 200111 into 96 well, sterile, tissue culture micro titre plates, and incubated at 37 C, 5% CO2 for 24 hours [0515] Growth media was removed and replaced with assay media {.RPMI 1640 without phenol red, 2mM L-glutamine + 10AM forskolin}. Test compounds were screened against a challenge of 100nM dexamethasone. Compounds were serially half log diluted in 100% (v/v) dimethylsupfoxide from a 10mM stock. Then an 8-point half-log dilution curve was generated followed by a 1:100 dilution into assay media to give a 10x final assay [compound]: this resulted in final assay [compound] that ranged 10 to 0.003AM in 0.1% (v/v) dimethylsulfoxide.
[0516] Test compounds were pre-incubated with cells in micro-titre plates for 30minutes at 37 C, 5/95 (VA') CO2/air, before the addition of 100nM dexamethasone and then subsequently for 20 hours to allow optimal TAT induction.
[0517] HepG2 cells were then lysed with 30i of cell lysis buffer containing a protease inhibitor cocktail for 15 minutes at 4 C. 155111 of substrate mixture was then added containing 5.4mM Tyrosine sodium salt, 10.8mM alpha ketoglutarate and 0.06mM pyridoxal 5' phosphate in 0.1M potassium phosphate buffer (pH 7.4). After 2 hours incubation at 37 C
the reaction was terminated by the addition of 1.5 1 of 10M aqueous potassium. hydroxide solution, and the plates incubated for a further 30 minutes at 37 C. The TAT activity product was measured by absorbance at X, 340nm.

05181 1050 values were calculated by plotting % inhibition (normalised to 100nM
dexamethasone TAT stimulation) v. [compound] and fitting the data to a 4 parameter logistic equation. 1C, values were converted to Ki (equilibrium dissociation constant) using the Cheng and Prusoff equation, assuming the antagonists were competitive inhibitors with respect to dexamethasone.
Table 1. Activity Data Ri..,e0 015) ek (R2)14 GR.
Example RI RI* Ring J R2 11 IF T.,µ -r __...........,...____, hi iitii ng,,...,...,...,...õ
bit. 13 pyridin-2-y1 pyridin-3-y1 6-C1 0 4 -s-iTh;.nµ,.
IM. 14 thiazo1-2-y1 pyridin-3-y1 6-CI 0 4-F-plieny1 - __________________ 1 pyridin-2-y1 phenyl 4-CF; o 4- F-phellyi ---+ +++
1\
' !11-imid azol-1 ,1 1-Me phenyl 4-CF3 0 4-F-phellyi +1- i-1-2-y1 , ___________________________________________ i pyridin-3- yl phenyl 4-CF; 0 4-F-phony! .4-1- +
I C tInazol-2-y1 phenyl 4-CF3 0 4 ..;-:.. rh(11µ,. ---- -H-+
.. ____________________________________________________________________ I 0 i )xadiazol-2- 5-Me phenyl 4-CF; 0 4 -7:-:-,i:; RH
YI
I E exazol-4-y1 phenyl 4-CF3 0 4-F-phenyi +++ ++
1 __________________ .
i F exazol-2-y-1 phenyl 4-CF; 0 4-F-phenyl +++ 1-+
____... ____________ 1 0 tbran-2-y1 phenyl 4-CFI o 4-F-phenyl -H-+ ++
I! thiophen-2-y1 phenyl 4.-CF 0 4-F-phenyl +++ ++
i I exazol-2-y1 phenyl 3-Me 0 4-F-phenyl +++ +1-pyTimidin-2-1.1 phenyl 3-Me 0 4-F-phenyl +++ ++
YI
1K pyridin-2-y1 4-0Me phenyl 3,5-di fluor 0 4-F-phenyl -I-H- +++

Example R1 Rh` Ring J 1(2 TAT
binding IL pyridin-2-y1 4-a phenyl 3,4,5-it-Ultimo 0 4-F-phenyi 4 -- 4. 4.4. +.
1M pyridin-2-y1 4-0Me phenyl 3,4,5-tri fluor 0 4-F-phenyl - i ---. , 2 pyridin-2-y1 phenyl 4-F 0 4-F-phenyl -F++ ++4-2A thiaz.o1-2-y1 pheny 1.-F 1 4-F-phenyl +++
-i-, tetrahydrefuran-2R thiaz.o1-2-y1 , 1 4-F-phenyl -H- +
2-y1 2C pyridin-2-y1 phenyl 2-Me 0 4-F-plicnvi +-+ -H-+
2D pyridin-2-y1 phenyl 4-Et 0 4-F-phenyl +++ +1-4-213, pyridin-2-y1 phenyl 3-Me 0 4-F-phenyl +.-4 ++4 2F pyridin-2-y1 phenyl 3-CI 0 4-F-phenyl '4-'4 +-H-'G pyridin-?-y1 phenyl -4-0Mr.= I) 4.-F-phenyl +++ +-H-. ______________________________ I I pyridin-2-y1 phenyi 3-F, 4-CI 0 4-F-phenyl +++
+++
.._ _____________________________________________________________ 21 pvridin-2-y1 phenyl 4-0Me 0 4-F-phenyl +++ +-H-. _______________________________________________________________ 2J pyridin-2-y1 phenyl 3-F, 4-Me 0 4-F-phenyl +++
+++
2K pyridin-2-y1 plien 'y! 0 4-F-phenyl +++
4++
2L pyridin-2-y1 phenyl 2-F 0 4-F-phenyl -1-1 .............................. , 2M pyridin-2-y1 11-1-pyrazol-4-y i 1 -Me 0 4-F-phenyl +++ ++
2.N pyridin-2-y1 pyridin-3-y1 6-CF 3 0 4-F-pheilyi +++ +4-i-2() pyridin-2-y1 phenyl 4-Me 0 4-F-phenyl +++ +++
2P pyrklin-2-y1 phenyl 3-C:F3, 4-F 0 4-F-phenyl +4-+++
2Q pyridin-2-y1 phenyl 4-CN 0 4-F-phenyl +++ -1-1-.7 tZ pyridin-2-y1 pyridin-3-y1 6-0Me 0 4-F-phenyl +++ +4+-- .
tetrahydro-20-pyridin-2-y1 pyran-4-y1 0 4-F-phenyl + +

Example R1 lea Ring J 1(2 GR
n le TAT
binding , _______________________________________________________________ 21 pyridin-2-y1 eyelohexyl 0 4-F-phcnyi 4.
213 pyridin-2-y1 4-CF 3 1H-pyrazol-5-y1 1-Et 0 4-F-phenyl - 44+-, ..
2V pyridin-2-y1 4-CF3 1H-pyrazol-4-y1 3,5-dinxtityi 0 4-F-phenyi + -H-1V pyridin-2-y1 4-CF3 111-imidazol-4-y1 0 4-F-phenyl + ++
3 pyridin-2-y1 pyridin-3-y1 6-morpholine 0 4-F-phenyl +++ -1-4-4 itil:.,r-,, -,- -. pyridin-3-y1 6-PYITtlii(litl- 0 4-F-phettyl +++ +
i _______________________________________________________________ thiazol-2-y1 - phen yi -1 -I' 0 4-F-phenyl +++ -H-SA thiazol-2-y1 phenyl 34. 0 4-F-phenyl +++ +++
5B thiaz.o1-2-yl phenyl 4-42N 1 4-F-phenyl +++ +
f' pyrittin-?-y1 phenyl 1-043 I) 4-F-phenyl +-H- -H-+
111-1.2 4-5ll = ' 1-Me phenyl 4-CF3 0 4-F-phenyl +++ +
tri azol = 5-y1 .
:51i pyrazin-2-y1 phenyl 4-CFI 0 4-F-pheny1 ++-i- ++
5F pyriciin-2-y1 1 pyridin-3-y1 5-1. 0 4-IF-phenyl +++ ++
50 pyridin-2-y1 phenyl 3-F 0 4-F-pheny1 +++ ++4"
51-1 pyridin-2-y1 5-0Me phenyl 4-CF. 0 1.- i-i-phenyl 4-4- 4-1-'-51 thiazol-5-y1 phenyl 4-CF3 0 4-1:-phettyl +++ +
. .
:5.1 thiazol-2-y1 pyridin-3-y1 5-F 0 4-F-phenyl .... ____________________________________ 4-pyrrolidin-6 thiazol-2-y1 phenyl 0 4-F-phenyl -H- +-1-1-y1 ¨
3-pyrrol id in-6A thiazol -2 -y1 phenyl 0 4-F-phenyl +-++ A-1 -y1 7 thiazo1-2-y1 pyridin 5-pipetidin- 1--3-y1 0 4-F-pheuyi +++ 1H-'7 =\ thiazol-2-y1 - pyridin-3-y1 0 4-F.-phenyl ++4- ++

--.- .
5-pyrrolidin-pyridin-2-y1 pyridin-3-y1 6-PYm)lidin- 0 1-y1 4-F-phenvi +++ +

Example IIII Rla Ring,! le II R3 GIZ
TAT
binding 9 thiazol-2-y1 pyridin-3-y1 fluoropyrrolid 0 4-F-pilelly , in-1-y1) ,, . .. . .
pyridin-2-y1 phenyl 4-pyrrolidin- v 4-!--pheny i 1- -4- 4-1 -yi i OA pyridin-2-y1 pyridin-3-y1 5-p iperidi n-1- 0 4-1Lpheily I 4-- l= .i = 4. 4.=
Y I
______________________________ ...- ¨
101i pyridin-2-y1 pyridin-3-y1 5-pyrrolidin-0 4-F-phen _.......
yl : E- +4- +
11 thiazo1-4-34 phenyl 4-CF3 0 4-F-phenyl 4-14 ++
1 1 A pyridin-2-y1 phenyl 4-C1 0 4-F-phenyl +4+
++4-... _____________________________________________________________ 1 I 13 pyridin-2-y1 I phenyl 3-Me, 4-0Me 0 4-F-phenyl +++ +++
I IC. pyridin-2-y1 phenyl 3-C1, 4-0Me 0 4-F-phenyl +++ ++
.... __ I ID pyridin-2-y1 phenyl 3-F, 4-0Me 0 4-F-phenyl ++4-++4-1 1 F. pyridin-2-y1 phenyl 2-F, 4-Me 0 4-F-phenyl 1-1-F
++
1 [.= thiazol-4-y1 phenyl 3-Me 0 4-F-phenyl +4+
++
- _______________________________________________________________ I 1G pyridin-2-y1 phenyl 3-C.N 0 4-F-phenyl +++ -H-+
, _______________________________________________ t---1 il pyridin-2-y1 phenyl 4-0CHF2 0 4-F- phcilyi +-+ +-I-I II pyridin-2-y1 phenyl 3-0CF3 0 4-F-pheny! -i --- .4. +++
, _______________________________________________________________ 11:.1 pyridin-2-y1 phenyl 3,5-di tluom 0 4-F-phenyi +++
+-i-+
I 1K thia.e.01-4-y1 phenyl 4-Me 0 4-F.-phenyl .4-14 +4+
I IL pyridin- 2- yl phenyl 3-0CHF2 0 1.- i".-phenyl -I-i-i- 4-1-4-1 IWI pyridin-2-y1 phenyl 3,4-di methyl 0 4-F-pheny I
+++ -I-H-I IN pyridin-2-y1 phenyl 3,5-dimethyl 0 4-F-phenyl +++ +++
110 pyridin-2-y1 pyridin-2-y1 6-Me 0 4-F-phenyl +-+ i-i-I I P pyridin-2-y1 pi:,.]zr,i 3,4-difluoro 0 4-F-pheny1 I
I IQ pyridin-2-y1 i !)!..: 3,4,5-1rilluoro 0 4-F-phenyl +++ -I-I-+
- _______________________________________________________________ i' .15 Example R1 Rh` Ring J 1(2 GR
TAT
binding 11 R pyridin-2-y1 phenyl 3-C1, 4-F 0 4-F-phenyi --- 4-+-F.+.
I1 pyridin-2-y1 4-Me phenyl 3-Ctn: 4-F-phenyl - ----f-4-+.
1 11. pyridin-2-y1 4-Me 1 H-pyrazol-4-y1 1-Me 4-F-phenyi -H-+
1U pyridin-2-y1 4-Me phenyl 3,4-di fluor 0 4-F-phenyl +4+ +++
I I V nyridin-2-y1 4-Me 11-1-imida7ol-4-y1 1-Me 0 4-F-phenyl ++
1 1W pyriclin-2-yl 4-N), = pileuy I 3,5-di fluoro 0 4-F-phenyl +++ +++
1 I X pyridin-2-y1 4-Me phenyl 3,4,5-tri fluor 0 4-F-phenyl ++4-1 1Y pyridin-2-y1 phenyl 3-S02Me 4-F-phenyl +++ -H-1 :17.. pyridin-2-y1 phenyl 3-0O211 0 4-F-phenyl 11AA pyritlin-/-y1 phenyl 1-C1-120Me I) 4-1-phenyl +-H-4-inethyl-3,4-dihydro-2H-1 1A13 pyridin-2-y1 pyrido[3,2-13][1,4]oxazin-7-y1 0 4-F-phenyl +++ ++
1 lAC pyrklin-2-y1 phen:v I 2,3,4-tritluoro 0 4-F-phenyl +++ +++
11 AD pyridin-2-y1 pyridin-2-y1 6-CF3 4-F-phenyl 4-4-+
++4-1 1.AE pyridin-2-y1 4-Me pyridin-2-y1 0 4-F-rhcnyi ----i 1 pyridin-2-y1 phenyl 3,4-diehloro 4- F.-pi ICrly +++
I I AG pyridin-2-y1 4-Me phenyl 4-F-pho ly --- -I 1AI-I pyridin-2-yl 4-Me 1 H-pyrazol-4-y1 1-Et 4-F-pheny I +++ +++-1 1 Al pyridin-211 4-Me I H-pyrazol-4-y1 1 ,S-ditnethyl 0 4-F-phenyl 4-++ +++
ii Al pyridin-2-y1 4-Me 1 H-pyrazol-5-y1 I -Me 0 4-F-phenyl ++4-I 1.AK. pyridiii-2-y1 4-Me 1H-pyrazol-3-y1 I-Me 0 4-F-plienyi -i-F+ 44+
11AL pyridin-2-y1 4-Me phenyl 3-Me, 4-F 0 4-F-phenyl Example ;1" Ring J 11 R3 GR
TAT
binding õ .
11AM pyridin-2-y1 4-Me 4-methy1-3,4-1ihydro-2H-0 4-P-1)11;211r pyrido[3,2-b][1,4]oxazin-7-y1 1 IAN pyridin-2-y1 4-Me 2,3-dihydrobenzofuran-5-y1 0 4-F-phenyl ++1 1 IA0 pyridin-2-y1 4-Me I -methylindolin-2-one-5-y1 0 4-F-phenyl +++
AP pyridin-2-y1 4-Me phenyl 3 -,S0-.Me 0 4-F-phenyl -H-+.
+4.4 'AO pyridin-2-y1 4-Me 1H-pyrazol-4-y1 1,3-dimethyl 0 4-1:- phcilyi Ii=
1 1AR pyridin-2-y1 4-Me 2,3-dihydrobenw[h][1,4]dioxin-0 4-F-phenyl "4"'+
6-y1 11AS pyriditt-2-y1 4-Me phenyl 3-F, 4-CF3 0 4-F-phenyl 11 AT pyridin-2-y1 phenyl 3-F, 4-CF3 0 4-F-pheny1 1 IAU pyridin-2-y1 4-Et. phenyl 3-CN 0 4-F-phenyl .1 11A.V pyridin-2-y1 p 6-CF3 0 4-F-phenyl +++.
II AW pyridin-2-y1 4-Me phenyl 3-0O21-1 0 4-F-phenyl +=-+
11AX pyridin-2-y1 4-Me isoxazol-4-y1 3,5-dimethyl 0 4- F-1); lenyi ... - -1.
I IAY pyridin-2-y1 1H-pyrazol-4-y1 1-Et 0 4-F-phenyl +-+
++
I 1AZ pyridin-2-y1 phenyl 3-CF3 0 phenyl 4-44 +4 I IRA pyridin-2-y1 4-Me III-pyrazo1-5-y1 1,3-dimethyl 0 4-F.-phenyl 44+ +++
I 11313 pyriclin-2-y1 4-Me 2-CF; 0 4-F-phenyl 4+-F
...........---.--------------------------.4-IBC pyriditt-2-y1 4-Me pyridin-2-y1 4-CF; 0 4-F-phenyl +4+ +++
11BD pyridin-2-y1 4-Me 1H-pyrazol-4-y1 5-Me 0 4-F-phenyl +++ -H-I 1BE pyridin-2-y1 pyridin-4-y1 2-CF3 0 4-F-phenyl +++
+4 Example R1 Ring J 1(2 GR
binding 11 Ill : pyridin-2-y1 phenyl 3-CF, 4-C1 0 4-F-phettyl 4-4 +.1-- _______________________________________________________________ IW pyridin-2-y1 phenyl 3-C1, 4-Me 0 4-F-phenyl 4-4.4-+4-+-I I pyrii.iiii-4-y1 pyrrolidi phenyl 3,4-di fluor 0 4-F-phenyl 4--y I psTid i 2-y1 4-CF, 1H-pyrazol-3-y1 1-Me 0 4-F-phenyl +++ +++
I 1BJ pyridin-2-y1 1H-pyrazol-3-y1 1-Me 0 4-F-phenyl -H-+ ++
1 :1BK pyridin-2-y1 4-CF3 1H-pyrazol-4-y1 5-Me 0 4-F-phenyl +4+ +++
1113I- PYridin-2-y1 4-CF3 phenyl 3-CN 0 4-F-phenyl 44+ +++
I BM pyridi '.-y1 4-CF:; 11-1-pyrazol-5-y1 1-Me 4-F-phetty1 +++ ++1-. ___ 11BN pyridin-2-y1 4-CF3 1H-pyrazol-4-y1 1,5-dimethyl 0 4-F-phony! -(-1-4- 4+4-11W) pyridin-2-y1 4-CF3 1H-pyrazol-4-y1 0 4-F-phenyl 4--1+ +-i+
11BP pyn (i) ti-2-y1 I 11-pyrazol-4-y1 1-Me, 3-CF3 4--F.-phenyl +++ +
11BQ pyrirlin- 2-yl 4-CF; 3,4,5-1ri tliloro 0 4-F-phenyi +
-i BR pyridin-2-y1 4-CF.; 11-1-pyrazol-3-y1 1-Me -- 0 -- 4-Cl-phony) -- +++
11BS pyridin-2-y1 1H-pyrazol-4-y1 0 4-F-phony!
11BT pyridin-2-y1 11-1-pyrazol-3-y1 1-Me 0 4-CF3-phenyi 11BU thiazol-4-y1 phenyl 3,4-di fluor 0 4-F-Dheny 1 +4-1 113V pyridin-2-y1 4-CF3 1 II-imiclazol-4 -yl 1,2-dinxthyl 0 4 --4-.=;-= = i =;==i=..
11BW pyridin-2-y1 4-CF3 1H-imidazol-5-y1 1,2-dimethyl 0 4-F-phenyl ++
11BX pyridin-2-y1 4-CF3 1.11-imidazol-2-y1 1-methyl 41 4-F-phenyl +++
BY pyridin-2-y1 4-CF3 1-ethyl 4-F-phenyl +++
+++
I 1BZ thiazol-4-y1 1I-1-pyrazol-4-y1 1-ethyl 0 4-F-phenyl +++ ++
11CA pyriciiii-2-y1 1 y razol-4-y1 1 -propyl 0 4-F-phenyl 1-1 .1. . -1. +

Example R1 12111 Ring J 1(2 11 R: G R .
binding .rAT
1 ICH pyridin-2-y1 I H-pyrazol-4-y1 - 4- -i-methoxyethyl) 1 I CC pyrazol-4-y1 I -Me phenyl 3,4-dichloro 0 4-F-phenyl 4-4.
11CD pyridin-2-y1 1H-pyrazol-4-y1 I-isopropyl 0 4-F-phcnyi ; I-++4- ++4-11CF, pyridin-2-y1 4-CF3 1,2,3-triazoly1 methyl 0 4-F-phenyl -H-1:ICG
+++ ++4-+++ -H-4-1 ICH, I ICI, pyridin-2-y1 1,2,3-triazoly1 ethyl 0 4-F-phenyl -H-++-I- -1-1-+++ +-H-i Mc pyridin-2-y1 4-CF3 1,2,3-trie2oly1 olly1 o 4-F-phenyi 4-4-i 1CM
+++ -H-F
4--.+ +-H-1 ICN, I 1CO, pyridin-2-y1 1,2,3-triae.oly1 propyl 0 4-F-phenyl ++

-i-H- -F-H-.. ______________________________________________________________ +4+ +4+
11CQ, 11CR, thiaz.o1-4-y1 1,2,3 -triazoly1 propyl 0 4-F-phenyl I I CS
-H-F
++-I- +4-I-I 1CT, 1 ICU, pyridin-2-y1 1,2,3-triazoly1 isopropyl 0 4-F-phenyl 1:ICV
+4+ ++
11CW thiazo1-4-y1 1 H-pyrazol-5 -y1 1 -cthyl U 4-F-phc;tty ++

Example R1 12111 Ring J 1(2 R3 GR
TAT
binding 1 1CX pyridin-2-y1 4-CF3 111-pyrazol-4-y1 1-propyl U 4-F-pheny1 -i.+
= 11CY thiazol-4-y1 1H-pyrazol-4-y1 1-methyl 0 4-F-pheny1 ++
11CZ thiazol-4-y1 1H-pyrazol-4-y1 1-propyl 4-F-phenyi +++ +++
1 IDA thiaz.o1-4-y1 1,2,3 -trimly! methyl o 4-F-phenyl 14+
11Dli pyridin-2-y1 12,3-triftzoly1 methyl U 4-F-phenyl 1 I DC pyridin-2-y1 4-CF3 1,2,3-triazoly1 propyi U 4-F-phenyl 1+ ++-F
12 thiazol-2-y1 phenyl 3-CF3 0 4 -P-phenyi 4-1+ +-14.
thiazol-2-y1 phenyl 3-Me 4-F-phenyl +++ +++
121i thiaz.o1-2-y1 phenyl 3-0Me o 4-F-phenyl -H- -1-+
12C thia7n1-2-y1 phenyl 4-Me, 1-F 4-F-phenyl +-H- -H-.. ______________________________________________________________ 12D thia-zo1-2-yl phenyl 0 4-F-phenyl +++
=
12E thiazol-2-yl phenyl 3-C1 0 4-F-phenyl +++ ++
12F pyridin-2-y1 5-Me phenyl 3-Me 4-F--phenyl +++ +++
12(1 pyridin-2-y1 4-Me pi leil.y1 3-Me ) 4-F-phen yl +++ +++
1214 pyridin-2-y1 6-Me phenyl 3-1V10 +,) 4-F-phonyl -1--H-121 linazol-2-y1 phenyl 3-CF3, 4-F 0 4-F-phenyl ++4- ++
12J thiazol-2-y1 phenyl 3,21,5-trifluoro 0 4-F-phenyl ++4- ++
12K thiazol-2-y1 phenyl 3-F, 4-CF-3 0 4-F-phenyl +-++ ++
12L thiazol-2-y1 5-Me phenyl 3-(.F, 0 4-F-phenyl +++ 44+
12M thietzol-2-yl 4-Me 0 4-F7-phenyl -H- -I-1-- _______________________________________________________________ 12N thiazol-2-y1 phenyl 3,4-diehloro 0 4-F-phenyl -4+ +++-120 tthiazol-2-yl 5-Me phenyl 3.4 -dilk:up 0 el-F-phenyl4-4+4+4-Example R1 Rh` Ring J 1(2 TAT
binding 12P thiazoi-2-y1 phenyl 3,4-difluoro 0 4-F-pheny I
4 -- 4. +4-. 12Q thiazol-2-y1 5-Me phenyl 3,4-difluoro 0 4-F-phenyl - +4-+.
. ..
12R thiazol-2-y1 5-Me phenyl 3-F, 4421 1) 4-F-phenyl 4-1- +++
___________________ i ¨ ______ 12S 1hiaz.o1-2-y1 5-Me 1H-pyrazA31-3-y1 1-Me 0 4-F-phenyl +4+ ++4-, _______________________________________________________________ .
12T thiaz.n1-2-y1 5-Me 1H-pyrazol-4-y1 1-Me 0 4-F-phenyl +++ +++
12U thiazoi-2-yl 5-Me 1H-pyrazol-5-y1 1,3-dimethyl 0 4-F-phetty1 + ++
_ .
12V thiazol-2-y1 5-Me 1H-pyrazol-5-y1 1-Me 0 4-F-phenyl ++ ++
12W thiazol-2-y1 114-pyrazo1-5-y1 1-ethyl 0 4-F.-phenyl +
+
¨ ____________ 12X thiaz.o1-2-y1 I 11 -pyrazol-4-y1 1-ethyl 0 4-F-phenyl +4+ 4-1-1V thif47111-7-y1 1 1-T-pyrszol-4-y1 1 -pmpyl I) 4-1-phenyl -F-H- +-H-, .........
12Z tinazoi-2-y1 1,2,3-triazoly1 methyl (1 4-F-phony! -F-F
+
12AA thiazo1-2-y1 1,2,3-triazoly1 propyl 0 4-F-phenyl +++ ++
, 1H-imidazol-13 I-Me phenyl 4-Me 0 4-F-phenyl -H- -H-2-y1 ____ = _________________________________________________________ 111-imidaz1ol -13A 1-Me pi te;ly 1 3-Me 1) 4-F-pheny1 +4+
++
2-y

14 pyridin-2-yI pheii:, i 3 (..i )!%:Nle.: 0 1.-1-phenyl -I-4-1- -1-4-

15 pyridin-2-y1 4-CF:; 11-1-pyrazol-4-y1 I -F.t 0 44F-phenyi -+ ++1-. _______________________________________________________________ ¨
i )A pyridin-2-y1 phenyl 3-CF3 0 pyridin-3-y1 4--,4-+4-15B pyridin-2-y1 phenyl 3,4-diehloro 0 phenyl +4+ 14+
¨ _______________________________________________________________ 3,4-15C pyridin-2-y1 phenyl 3,4-dichloro 0 1-H- ++
difluorophenyl _ _______________________________________________________________ 15D pyridin-2-y1 phenyl ,5-difluoro, 0 4-F-phenyl -i-i- +++
4-methoxy

16 pyridin-2-y1 pyridit)-3-yl 6-NMe2 0 4-F-phenyl '- --- - .4.-F"
yrid in-2(1H)-

17 pyridin-2-y1 p 1-Me 0 4-F-phenyi +
one-5-y1 Example R1 Rh` Ring J 1(2 le GR
. TAT
binding

18 pyridin-2-y1 4-CF 11-1-pyrazol-4-y1 I -M U
4-F.-phenyl 4-1- 4. +++.
-

19 th iazoi-4-y1 , phenyl 3,4-diehloro 0 4-F-phenyl +++ +++
In Table 1, OR Binding compounds with a K1 value of less than 0.5 nM are designated with ++
compounds with a KJ value from 0.5 nM to less than 1.0 nM are designated with ++; and compounds with a KI value of at least 1.0 nM are designated with +. TAT
activity with a Ki value of less than 20 nM are designated with +++, compounds with a K1 value from 20 nM to less than 100 nM are designated with ++; and compounds with a Ki value of at least 100 nM are designated with 4.
Example 22. Cell Transrepression Assays 105191 The following protocol describes assays for measuring the effect of either OR agonists or antagonists on IL-1 3 stimulated IL-6 production by A549 cells.
105201 In the GR. antagonist mode of the assay compounds are tested for their ability to reverse the suppression of 1L-10 stimulated 1L-6 production by dexamethasone.
Conversely, in the OR.
agonist mode of the assay compounds are tested for their ability to directly inhibit IL-113 stimulated 1L-6 production. These assays were adapted from a protocol outlined by Ali et al., J.
Med. Chem. (2004), 47, 2441-2452.
105211 A549 cells were routinely cultured in DMEM media supplemented with 10%
(v/v) foetal bovine serum and 2 triM L-glutamine at 37 C, 5 %/95% (v/v) CO2lair (Standard incubation Conditions). For assay use, cells were counted and the suspension diluted in DMEM
supplemented with 2 mM L-glutamine (Assay Media) to 0.66 x 106 cells/ml. This cell preparation was then used to seed sterile, tissue culture treated, 384 well plates (20,000 cells/well), which were subsequently kept under Standard Incubation Conditions for 1 hour.
105221 Compounds were solubilised in DMSO to generate a 10 mM stock solution.
A range of 8 test concentrations were generated by diluting the stock solution in DMSO to 240 alM, followed by 7 serial half log dilutions in DMSO. These test compound solutions were diluted 40-fold into Assay Media prior to addition to the cells to give a range of final assay compound concentrations of 10 to 0.003 laM in 0.25% (v/v) DMSO.
[0523] Note that the standard GR agonist dexamethasone was tested at concentrations ranging from 100 to 0.03 nM. Compounds were screened for GR antagonism of an EC80(10 nM) dexamethasone stimulation.
[0524] Compounds were pre-incubated with cells for 1 hour using Standard Conditions as previously described, prior to the addition of 10 nM dexamethasone (antagonist mode) or Assay Media (agonist mode) and then incubated for a further hour.
[0525] Cells were then stimulated with IL-I 1J (final assay concentration 3 ng/ iL) and incubated for 18 hours to allow sufficient IL-6 to be produced.
[0526] IL-6 in the cell media was measured using an AlphaLISA detection assay (Perkin Elmer). Raw data were converted to IL-6 concentrations by interpolation of test data against an IL-6 standard curve using GraphPad Prism software.
[0527] For the agonist mode assay, IL-6 values were normalised to the maximal effect of the full agonist dexamethasone and compound concentration effect curves were fitted to a 4 parameter logistic equation to determine EC50 and maximal effect values.
[0528] For the antagonist mode assay, IL-6 values were normalised to the effect of 10 nM
dexamethasone inhibition of IL-6 production, such that 100% inhibition represented complete reversal of the dexamethasone suppression of IL-6. Compound IC50 values were determined by plotting compound concentrations against % inhibition and fitting the data to a 4 parameter logistic equation. Compound Ki (inhibitor dissociation constant) values were estimated by correcting the IC50 values using the Cheng-Prusoff equation, assuming that all compounds were competitive GR antagonists with respect to dexamethasone.
[0529] Although the foregoing invention has been described in some detail by way of illustration and Example for purposes of clarity of understanding, one of skill in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. Where a conflict exists between the instant application and a reference provided herein, the instant application shall dominate.

Claims (26)

WHAT IS CLAIMED IS:

1. A compound having the formula:
wherein R1 is a heteroaryl ring having from 5 to 6 ring members and from 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S, optionally substituted with 1-4 groups each independently selected from R1a;
each R1a is independently selected from the group consisting of hydrogen, C1-6 alkyl, halogen, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -CN, N-oxide, C3-8 cycloalkyl, and C3-8 heterocycloalkyl;
ring J is selected from the group consisting of a cycloalkyl ring, a heterocycloalkyl ring, an aryl ring and a heteroaryl ring, wherein the heterocycloalkyl and heteroaryl rings have from 5 to 6 ring members and from 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S;
each R2 is independently selected from the group consisting of hydrogen, C1-6 alkyl, halogen, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkyl-C1-6 alkoxy, -CN, -OH, -NR2aR2b, -C(O)R2a, -C(O)OR2a, -C(O)NR2aR2b, -SR2a, -S(O)R2a, -S(O)2R2a, C3-8 cycloalkyl, and C3-8 heterocycloalkyl, wherein the heterocycloalkyl groups are optionally substituted with 1-4 R2c groups;
alternatively, two R2 groups linked to the same carbon are combined to form an oxo group (=O);
alternatively, two R2 groups are combined to form a heterocycloalkyl ring having from to 6 ring members and from 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S, wherein the heterocycloalkyl ring is optionally substituted with from 1 to 3 R2d groups;

R2a and R2b are each independently selected from the group consisting of hydrogen and C1-6 alkyl;
each R2c is independently selected from the group consisting of hydrogen, halogen, hydroxy, C1-6 alkoxy, C1-6 haloalkoxy, -CN, and -NR2aR2b;
each R2d is independently selected from the group consisting of hydrogen and C1-6 alkyl, or two R2d groups attached to the same ring atom are combined to form (=O);
R3 is selected from the group consisting of phenyl and pyridyl, each optionally substituted with 1-4 R3a groups;
each R3a is independently selected from the group consisting of hydrogen, halogen, and C1-6 haloalkyl;
subscript n is an integer from 0 to 3;
or salts and isomers thereof.

2. The compound of claim 1, wherein R1 is a heteroaryl ring having from 5 to 6 ring members and from 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S, optionally substituted with 1-4 groups each independently selected from R1a;
each R1a is independently selected from the group consisting of hydrogen, C1-6 alkyl, halogen, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -CN, C3-8 cycloalkyl, and C3-8 heterocycloalkyl;
ring J is selected from the group consisting of a cycloalkyl ring, a heterocycloalkyl ring, an aryl ring and a heteroaryl ring, wherein the heterocycloalkyl and heteroaryl rings have from 5 to 6 ring members and from 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S;
each R2 is independently selected from the group consisting of hydrogen, C1-6 alkyl, halogen, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -CN, -NR2aR2b, C3-8 cycloalkyl, and C3-8 heterocycloalkyl, wherein the heterocycloalkyl groups are optionally substituted with 1-4 R2c groups;

R2a and R2b are each independently selected from the group consisting of hydrogen and C1-6 alkyl;
each R2c is independently selected from the group consisting of hydrogen, halogen, hydroxy, C1-6 alkoxy, C1-6 haloalkoxy, -CN, and -NR2aR2b;
R3 is selected from the group consisting of phenyl and pyridyl, each optionally substituted with 1-4 R3a groups;
each R3a. is independently selected from the group consisting of hydrogen, halogen, and C1-6 haloalkyl; and subscript n is an integer from 0 to 3.

3. The compound of claim 1, wherein each R2 is independently hydrogen, C1-6 alkyl, halogen, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkyl-C1-6 alkoxy, -CN, -NR2aR2b, -C(O)OR2a, -S(O)2R2a, C3-8 cycloalkyl, or C3-8 heterocycloalkyl, wherein the heterocycloalkyl group has 5-6 ring members and 1 to 2 heteroatoms.

4. The compound of claim 1, wherein each R2 is independently hydrogen, methyl, ethyl, propyl, isopropyl, F, Cl, -CF3, CH2OMe, OMe, OCHF2, -CN, -NMe2, -C(O)OH, -C(O)NMe2, -S(O)2Me, pyrrolidine, piperidine or morpholine.

5. The compound of any one of claims 1 to 4, wherein each R1a is independently selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy and C3-8 heterocycloalkyl.

6. The compound of any one of claims 1 to 5, wherein ring J is selected from the group consisting of heterocycloalkyl, aryl and heteroaryl.

7. The compound of any one of claims 1 to 6, wherein ring J is selected from the group consisting of aryl and heteroaryl.

8. The compound of any one of claims 1 to 7, wherein ring J is selected from the group consisting of phenyl, pyridine, imidazole, pyrazole, triazole, tetrazole, thiadiazole, isothiazole, isoxazole, cyclohexyl, tetrahydrofuran and tetrahydro-2H-pyran.

9. The compound of claim 1 or 2, wherein R1 is a heteroaryl ring having from 5 to 6 ring members and from 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S, optionally substituted with 1-4 groups each independently selected from R1a;
each R1a is independently selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy;
ring J is selected from the group consisting of tetrahydrofuran, phenyl and pyridyl;
each R2 is independently selected from the group consisting of hydrogen, C1-6 alkyl, halogen, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -CN, -NR2aR2b, C3-8 cycloalkyl, and C3-8 heterocycloalkyl;
R2a and R2b are each independently selected from the group consisting of hydrogen and C1-6 alkyl;
R3 is selected from the group consisting of phenyl and pyridyl;
R3a is F; and subscript n is 0 or 1.

10. The compound of claim 1, 2, or 9, wherein R1 is a heteroaryl ring having from 5 to 6 ring members and from 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S, optionally substituted with 1-4 groups each independently selected from R1a;
each R1a is independently selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy;
ring J is selected from the group consisting of phenyl and pyridyl;
each R2 is independently selected from the group consisting of hydrogen, halogen, C1-6 haloalkyl, -CN and C5-6 heterocycloalkyl;

R3 is selected from the group consisting of phenyl and pyridyl; and R3a is F.

11. The compound of any one of claims 1 to 10, wherein R1 is selected from the group consisting of pyrrole, pyrazole, imidazole, triazole, tetrazole, furan, oxazole, isoxazole, oxadiazole, thiophene, thiazole, isothiazole, thiadiazole, pyridine, pyrazine, pyrimidine, and pyridazine.

12. The compound of any one of claims 1 to 11, wherein R1 is selected from the group consisting of 2-pyrrole, 3-pyrrole, 3-pyrazole, 4-pyrazole, 5-pyrazole, 2-imidazole, 4-imidazole, 5-imidazole, 1,2,3-triazol-4-yl, 1,2,3,-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,3,4-tetrazol-1-yl, 1,2,3,4,tetrazol-5-yl, 2-furan, 3-furan, 2-oxazole, 4-oxazole, 5-oxazole, 3-isoxazole, 4-isooxazole, 5-isooxazole, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, 2-thiophene, 3-thiophene, 2-thiazole, 4-thiazole, 5-thiazole, 3-isothiazole, 4-isothiazole, 5-isothiazole, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1,3,4-thiadiazol-2-yl, 2-pyridine, 3-pyridine, 4-pyridine, pyrazine, 2-pyrimidine, 4-pyrimidine, 5-pyrimidine, 6-pyrimidine, 3-pyridazine, 4-pyridazine, 5-pyridazine, and 6-pyrdazine.

13. The compound of any one of claims 1 to 11, wherein R1 is selected from the group consisting of pyrazole, imidazole, triazole, furan, oxazole, oxadiazole, thiophene, thiazole, pyridine, pyrazine and pyrimidine.

14. The compound of any one of claims 1 to 13, wherein R1 is selected from the group consisting of 1-pyrazole, 3-pyrazole, 4-pyrazole, 5-pyrazole, 2-imidazole, 4-imidazole, 5-imidazole, 1,2,3-triazol-4-yl, 1,2,3,-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 2-furan, 3-furan, 2-oxazole, 4-oxazole, 5-oxazole, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, 2-thiophene, 3-thiophene, 2-thiazole, 4-thiazole, 5-thiazole, 2-pyridine, 3-pyridine, 4-pyridine, pyrazine, 2-pyrimidine, 4-pyrimidine, 5-pyrimidine, and 6-pyrimidine.

15. The compound of any one of claims 1 to 14, wherein each R1a is independently selected from the group consisting of hydrogen, methyl, ethyl, trifluoromethyl, and methoxy.

16. The compound of any one of claims 1 to 15, wherein ring J is phenyl.

17. The compound of any one of claims 1 to 15, wherein ring J is pyridyl.

18. The compound of any one of claims 1 to 17, wherein R3 is 4-F-phenyl.

19. A compound, wherein the compound is:
(R)-(6-((6-chloropyridin-3-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(6-((6-chloropyridin-3-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6, 7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(1-methyl-1H-imidazol-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-3-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5, 6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methyl-1,3,4-oxadiazol-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a, 5, 6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(oxazol-4-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(oxazol-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(furan-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiophen-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(oxazol-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyrimidin-2-yl)methanone, (R)-(6-((3,5-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methoxypyridin-2-yl)methanone, (R)-(4-ethylpyridin-2-yl)(1-(4-fluorophenyl)-6-((3,4,5-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((3,4,5-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methoxypyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((4-fluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(6-((3-fluorobenzyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, ((4aR)-1-(4-fluorophenyl)-6-((((R/S)-tetrahydrofuran-2-yl)methyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-(o-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(6-((4-ethylphenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(6-((3-chlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((3-methoxyphenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(6-((4-chloro-3-fluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((4-methoxyphenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(6-((3-fluoro-4-methylphenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-(phenylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((2-fluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-tosyl-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(6-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-4-((1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)benzonitrile, (R)-(1-(4-fluorophenyl)-6-((6-methoxypyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(6-(cyclohexylsulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(6-((1-ethyl-1H-pyrazol-5-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, (R)-(6-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, (R)-(6-((1H-imidazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((6-morpholinopyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((6-(pyrrolidin-1-yl)pyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((4-fluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((3-fluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, (R)-4-(((1-(4-fluorophenyl)-4a-(thiazole-2-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)methyl)benzonitrile, (R)-(1-(4-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(1-methyl-1H-1,2,4-triazol-5-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyrazin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((5-fluoropyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((3-fluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methoxypyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-5-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((5-fluoropyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((4-(pyrrolidin-1-yl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((3-(pyrrolidin-1-yl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((5-(piperidin-1-yl)pyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((5-(pyrrolidin-1-yl)pyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((6-(pyrrolidin-1-yl)pyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, ((R)-1-(4-fluorophenyl)-6-((6-((R)-3-fluoropyrrolidin-1-yl)pyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((4-(pyrrolidin-1-yl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((5-(piperidin-1-yl)pyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((5-(pyrrolidin-1-yl)pyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone, (R)-(6-((4-chlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((4-methoxy-3-methylphenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(6-((3-chloro-4-methoxyphenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(6-((3-fluoro-4-methoxyphenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(6-((2-fluoro-4-methylphenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone, (R)-3-((1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)benzonitrile, (R)-(6-((4-(difluoromethoxy)phenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((3-(trifluoromethoxy)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(6-((3,5-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-tosyl-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone, (R)-(6-((3-(difluoromethoxy)phenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(6-((3,4-dimethylphenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(6-((3,5-dimethylphenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((6-methylpyridin-2-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(6-((3,4-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((3,4,5-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(6-((3-chloro-4-fluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-3-((1-(4-fluorophenyl)-4a-(4-methylpicolinoyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)benzonitrile, (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone, (R)-(6-((3,4-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone, (R)-(6-((3,5-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((3,4,5-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((3-(methylsulfonyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-3-((1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)benzoic acid, (R)-(1-(4-fluorophenyl)-6-((3-(methoxymethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((2,3,4-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((6-(trifluoromethyl)pyridin-2-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((6-(trifluoromethyl)pyridin-2-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone, (R)-(6-((3,4-dichlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone, (R)-(6-((1-ethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone, (R)-(6-((1,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-5-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone, (R)-(6-((4-fluoro-3-methylphenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone, (R)-(6-((2,3-dihydrobenzofuran-5-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone, (R)-5-((1-(4-fluorophenyl)-4a-(4-methylpicolinoyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)-1-methylindolin-2-one, (R) - ( 1-(4-fluorophenyl)-6-((3-(methylsulfonyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone, (R)-(6-((1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone, (R)-(6-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone, (R)-(6-((3-fluoro-4-(trifluoromethyl)phenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone, (R)-(6-((3-fluoro-4-(trifluoromethyl)phenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-3-((4a-(4-ethylpicolinoyl)-1-(4-fluorophenyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)benzonitrile, (R)-(4-ethylpyridin-2-yl)(1-(4-fluorophenyl)-6-((6-(trifluoromethyl)pyridin-2-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)methanone, (R)-3-((1-(4-fluorophenyl)-4a-(4-methylpicolinoyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)benzoic acid, (R)-(6-((3,5-dimethylisoxazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone, (R)-(6-((1-ethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-phenyl-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(6-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((2-(trifluoromethyl)pyridin-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)pyridin-2-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((5-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((2-(trifluoromethyl)pyridin-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(6-((4-chloro-3-(trifluoromethyl)phenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(6-((3-chloro-4-methylphenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(6-((3,4-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(2-(pyrrolidin-1-yl)pyridin-4-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((5-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, (R)-3-((1-(4-fluorophenyl)-4a-(4-(trifluoromethyl)picolinoyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)benzonitrile, (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-5-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, (R)-(6-((1,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, (R)-(6-((1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((3,4,5-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, (R)-(1-(4-chlorophenyl)-6-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, (R)-(6-((1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(6-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-1-(4-(trifluoromethyl)phenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(6-((3,4-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone, (R)-(6-((1,2-dimethyl-1H-imidazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, (R)-(6-((1,2-dimethyl-1H-imidazol-5-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-imidazol-2-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, (R)-(6-((1-ethyl-1H-imidazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, (R)-(6-((1-ethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(6-((3,4-dichlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(1-methyl-1H-pyrazol-4-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((1-isopropyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-1,2,3-triazol-5-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, (R)-(6-((2-ethyl-2H-1,2,3-triazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(6-((1-ethyl-1H-1,2,3-triazol-5-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(6-((1-ethyl-1H-1,2,3-triazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(6-((2-ethyl-2H-1,2,3-triazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, (R)-(6-((1-ethyl-1H-1,2,3-triazol-5-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, (R)-(6-((1-ethyl-1H-1,2,3-triazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((2-propyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((1-propyl-1H-1,2,3-triazol-5-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((1-propyl-1H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((2-propyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((1-propyl-1H-1,2,3-triazol-5-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((1-propyl-1H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((1-isopropyl-1H-1,2,3-triazol-5-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((1-isopropyl-1H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(6-((1-ethyl-1H-pyrazol-5-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((3-methoxyphenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, (R)-(6-((3-fluoro-4-methylphenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-(phenylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, (R)-(6-((3-chlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methylpyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(6-methylpyridin-2-yl)methanone, (R)-(6-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((3,4,5-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, (R)-(6-((3-fluoro-4-(trifluoromethyl)phenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methylthiazol-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylthiazol-2-yl)methanone, (R)-(6-((3,4-dichlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, (R)-(6-((3,4-dichlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methylthiazol-2-yl)methanone, (R)-(6-((3,4-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, (R)-(6-((3,4-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methylthiazol-2-yl)methanone, (R)-(6-((4-chloro-3-fluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methylthiazol-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methylthiazol-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methylthiazol-2-yl)methanone, (R)-(6-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methylthiazol-2-yl)methanone, (R)-(1-(4-fluorophenyl)-641-methyl-1H-pyrazol-5-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methylthiazol-2-yl)methanone, (R)-(6-((1-ethyl-1H-pyrazol-5-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, (R)-(6-((1-ethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-tosyl-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(1-methyl-1H-imidazol-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(1-methyl-1H-imidazol-2-yl)methanone , (R)-3-((1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)-N,N-dimethylbenzamide, (R)-(6-((1-ethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, (R)-pyridin-2-yl(1-(pyridin-3-yl)-6-43-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)methanone, (R)-(6-((3,4-dichlorophenyl)sulfonyl)-1-phenyl-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(6-((3,4-dichlorophenyl)sulfonyl)-1-(3,4-difluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(6-((3,5-difluoro-4-methoxyphenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(6-((6-(dimethylamino)pyridin-3-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-5-((1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)-1-methylpyridin-2(1H)-one, (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, (R)-(6-((3,4-dichlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone, or a salt or isomer thereof.

20. A compound, wherein the compound is:
(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, (R)-(6-((3,4-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(6-((3,4-dichlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, (R)-(6-((3,4-dichlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, (R)-(6-((3,4-dichlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methylthiazol-2-yl)methanone, (R)-(6-((3-fluoro-4-(trifluoromethyl)phenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone , (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-5-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, (R)-(6-((1-ethyl-1H-pyrazol-5-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, or (R)-(6-((3,4-dichlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone.

21. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 20 and a pharmaceutically acceptable excipient.

22. The pharmaceutical composition of claim 21, further comprising an anti-inflammatory glucocorticosteroid.

23. Use of a compound as defined in any one of claims 1 to 20 for modulating a glucocorticoid receptor.

24. Use of a pharmaceutical composition as defined in claim 21 or 22 for modulating a glucocorticoid receptor.

25. Use of a compound as defined in any one of claims 1 to 20 for antagonizing a glucocorticoid receptor.

26. Use of a pharmaceutical composition as defined in claim 21 or 22 for antagonizing a glucocorticoid receptor.